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Collaboration Opportunities

The basis of the NIH Oxford-Cambridge Scholars Program (OxCam) is the fostering and creation of collaborative research projects between NIH laboratories and laboratories at the University of Oxford or the University of Cambridge. Each student is responsible for choosing or creating a collaborative project that will constitute their doctoral research by electing one NIH mentor and one UK mentor who will work together to guide the student through the research process. Students can select from two categories of projects: self-designed or prearranged. 

Self-designed projects: Student can create de novo projects based on their own research interests. Students have the freedom to contact any PI at NIH or at Oxford or Cambridge to build a collaboration from scratch. The NIH Intramural Research Program (IRP) represents a community of approximately 1,200 tenured and tenure-track investigators providing a wealth of opportunity to explore a wide variety of research interests. For tips on choosing a mentor, please visit our Training Plan.

Prearranged projects: Investigators at NIH or at Oxford or Cambridge have already created collaborative projects which are described below.  In some cases, a full collaboration with two mentors is already in place, or in other instances only one side of the collaboration is identified and the student would be required to seek out a second mentor to complete the collaboration. Please note that project offerings are continuously updated throughout the year and are subject to change.

National Cancer Institute
National Center for Advancing Translational Sciences
National Center for Complementary and Integrative Health
National Eye Institute
National Heart, Lung, and Blood Institute 
National Human Genome Research Institute
National Institute on Aging
National Institute for Allergy and Infectious Diseases
National Institute of Child Health and Human Development
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Drug Abuse
National Institute of Environmental Health Sciences
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke
National Library of Medicine
Oxford
Cambridge

National Cancer Institute (NCI)

UK Mentor: Prof. Kilian Huber
University:  Oxford, Centre for Medicines Discovery
NIH Mentor: Prof. Jordan Meier (NCI)
Project listed date: November 2020
Project: Chemical biology tools to study crosstalk between cell metabolism and protein degradation

In order to maintain homeostasis in response to environmental changes such as nutrient availability, eukaryotic cells have evolved intricate mechanisms to quickly increase or decrease the activity of fundamental processes such as gene expression, protein expression and degradation. Indeed, several metabolites act as cofactors for important cellular enzymes that regulate e.g. chromatin state and serve as templates for posttranslational modifications flagging proteins for proteolysis via the ubiquitin-proteasome system. Consequently, the identification of metabolites and complementary binding domains has broadened our understanding of human physiology and contributed to the development of new medicines to treat malignant and inflammatory disease. The aim of this project is to systematically map protein-metabolite interactions on a proteome-wide scale by combining the development of specific metabolite-inspired affinity reagents with unbiased approaches such as thermal profiling to dissect metabolite signalling in the context of protein degradation pathways in various cell types. Applicants will have the opportunity to take advantage of a unique combination of synthetic organic chemistry and cell biology techniques to identify new potential drug targets and develop first-in-class ligands for key regulators of protein homeostasis.

NIH mentor: Dr. Curtis Harris (NCI)
UK mentor: Prof. Xin Lu (Oxford)
University: Oxford
Project listed date: August 2020
Project: Crosstalk between tumour suppressor p53 and inflammation in cancer

The tumour suppressor p53 is encoded by the most mutated gene in human cancers and there is extensive knowledge of its vital role in tumour suppression. However, the contribution of p53 to immune surveillance is less well understood. Cancer initiation and progression is influenced by inflammation, and it is increasingly important to understand interactions between inflammatory and tumourigenic pathways to improve cancer prevention and patient responses to immunotherapy. p53 activity is known to intersect with key inflammatory signalling pathways, including NFB, AP1, MAPK and JAK/STAT, suggesting p53 could have a pivotal role in immune surveillance. To expand knowledge in this important area, this project will investigate crosstalk between the p53 pathway and inflammation.

The project will use cutting edge technologies, including ex vivo 3D organoid co-culture models, to study interactions between cancer-initiating epithelial cells and immune cells. It will also harness recent advances in RNA-sequencing, single cell analysis and ChIP-sequencing, as well as a broad range of molecular cell biology techniques, to address the crosstalk between p53 and inflammation. The student will be able to leverage access to expertise and clinical samples in chronic inflammatory conditions – such as Barrett’s Oesophagus – that predispose patients to cancer. Oesophageal cancer and stomach cancer may be used as exemplar cancer types; these cancers have important unmet clinical needs and strong links to inflammation. This project may also extend to crosstalk of p53 with the immune system, such as in the context of immunotherapy for cancer: an emerging therapeutic strategy that is showing great success in some patients. The study will offer exciting opportunities to understand the details of the relationship between p53 and inflammation, which will be crucial for developing new approaches for early intervention to prevent cancer progression and for understanding responses to therapy.

References:
Chen S. et al. iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition. Proc Natl Acad Sci U S A. 116(35):17470-17479 (2019)
Owen R. et al. Single cell RNA-seq reveals profound transcriptional similarity between Barrett’s oesophagus and oesophageal submucosal glands. Nature Communications 9, 4261 (2018)
Turnquist C. et al. STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression. Proc Natl Acad Sci U S A. 111(27):9834-9 (2014)

NIH Mentor: Dr. Sam M. Mbulaiteye (NCI/DCEG)
UK Mentor: Prof. Ana Schuh
University: Oxford, Department of Oncology
Project listed date: October 2020
Project: The BL research is organized into four focus areas: a) epidemiology; b) infections; c) genetics, and d) tumor studies. The epidemiological studies seek to characterize the macro- and micro-geographical and spatial-temporal  patterns of endemic Burkitt lymphoma to generate new hypotheses about environmental risk factors. The infection focus seek to discover infection-related biomarkers of risk, focusing on unique serological profiles or discovery of high-risk genetic variants for EBV or Pf infection associated with eBL risk. The genetic studies (GWAS, exome, HLA) provide a powerful approach to complement questionnaire and serological methods with less concern for measurement error, reverse causality, and imperfect correlation with biology to disentangle the genetic architecture of eBL risk.  Finally, BL is a molecular disease with identifiable molecular sub-groups. The EMBLEM study provides an opportunity to collaborate with others on studies to develop a blood-based assay for BL diagnosis and molecular characterization. Students will be given the opportunity to spend time in East Africa with collaborating partners to be involved with data and sample collections.

The primary goals of EMBLEM are to investigate:
a) risk factors of BL in endemic populations in East Africa;
b) EBV and Pf immuno-profiles and other biomarkers associated with BL;
c) molecular characteristics of BL tumor genomes, B-cell receptor, and EBV variants; and
d) germline risk factors of BL using genome-wide association studies (GWAS) and exome sequencing
e) the association between BL and human leukocyte antigen (HLA) class I and II loci.

NIH Mentor: Dr. Christian Abnet (NCI/DCEG)
UK Mentor: Prof. Rebecca Fitzgerald
University: CambridgeMRC Cancer Unit
Project listed date: September 2019
Project: Genetics of squamous cell carcinoma - identifying high risk groups

NIH mentor: Dr. Amy Berrington de Gonzalez (NCI)
UK mentor: 
University:
Project listed date: September 2019
Project: 

NIH mentor: Dr. Eric Freed (NCI)
UK mentor: Prof. Andrew LeverProf. John Briggs
University: Cambridge
Project listed date: October 2020
Project: The Freed lab is interested in the assembly and release of HIV-1 from infected cells, Env incorporation, the host factors that both promote and restrict the late events in HIV-1 replication, and virus maturation.  The lab has a long-term program focused on developing maturation inhibitors, and has recently discovered a role for the HIV-1 envelope glycoprotein in conferring broad antiretroviral drug resistance. A new project is focused on cellular factors that block the function of a range of viral glycoproteins, including the spike protein of SARS-CoV-2.

NIH mentor: Dr. Ludmila Prokunina-Olsson (NCI)
UK mentor:
University:
Project listed date: September 2019
Project: Genetic and functional association of a novel human interferon, IFN-λ4, with human infections and cancer.

NIH Mentor: Dr. Louis Staudt (NCI)
UK Mentor: Prof. Carlos Caldas
University: Cambridge, Department of Oncology
Project listed date: September 2019
Project: 

NIH mentor: Dr. David Wink (NCI/CCR)
UK mentor: Prof. Jens Rittscher (Oxford)
University: Oxford
Project listed date: September 2019
Project: Comprehensive quantitative assessment of tissue biopsies in 3D

National Center for Advancing Translational Sciences (NCATS)

 

National Center for Complementary and Integrative Health (NCCIH)

NIH mentor: Dr. Lauren Atlas (NCCIH/NIDA)
UK mentor:
University:
Project listed date: September 2019
Project: Characterizing the psychological and neural mechanisms by which expectations and other cognitive and affective factors influence pain, emotional experience, and clinical outcomes.

National Eye Institute (NEI)

NIH Mentor: Dr. Kapil Bharti (NEI)
UK Mentor:
University:
Project listed date: September 2019
Project: Translation research on degenerative eye diseases using induced pluripotent stem cells.

NIH mentor: Dr. Kapil Bharti (NEI)
UK mentor: Prof. Colin Goding
University: Oxford, Ludwig Institute for Cancer Research
Project listed date: September 2019
Project: Developing Treatment Paradigms for Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is one of the leading causes of blindness among the elderly affecting over 30 million individuals world-wide. AMD initiates in the back of the eye because of dysfunctions in the retinal pigment epithelium (RPE), a monolayer of cells that maintains vision through maintenance of photoreceptor healthy and integrity. AMD can lead to severe vision loss and blindness in advanced stages – “dry” and “wet” forms. In the dry stage, the death of RPE cells triggers photoreceptor cell death and atrophy of the choroidal blood supply causing vision loss. It is thought that RPE cell death in AMD is triggered by the formation of sub-RPE protein/lipid deposits called drusen. Our recent work shows that drusen formation is initiated by reduced autophagic flux in RPE cells resulting in reduced ability of RPE cells to process intracellular “debris” that eventually gets secreted as drusen deposits. TFEB, a member of MiT family of transcription factors is a known master regulator of autophagy. Here, we propose to investigate the activity of transcription factor TEFB in our AMD cellular models of iPSC-derived RPE cells. We hypothesize that autophagy downregulation is triggered by post-translational changes in TFEB that affect its sub-cellular localization and reduce its transcriptional activity. Here, we propose to identify those changes in TEFB and discover signaling pathways that lead to its altered activity. Lastly, we will test the ability of our recently discovered FDA-approved drugs that stimulate TEFB activity to reduce drusen formation by increasing autophagy in iPSC-RPE AMD models. This work will lead to a better understanding of AMD pathogenesis and potentially retool existing  drugs to treat AMD patients.

NIH Mentor: Dr. Wei Li (NEI)
UK Mentor: Dr. Mike Murphy
University: Cambridge, MRC Mitochondrial Biology Unit
Project listed date: September 2019
Project: Mitochondrial regulations and their roles in metabolic adaptation in hibernation

National Heart, Lung, and Blood Institute (NHLBI)

NIH Mentor: Dr. Naoko Mizuno (NHLBI)
UK Mentor: Prof. Yvonne Jones
University: Oxford, Wellcome Trust centre for Human Genetics
Project listed date: October 2020
Project: 

The formation of neural network is essential for building a nerve system and to maintain its dynamic function. Neuronal cells extend their axons to connect to dendrites of partner neurons. The process is facilitated by axonal migration and controlled by the balance of the search for partner neurons vs the locking of axon-dendrite connections. This balance is maintained by two signaling pathways relying on the integrin receptor (mode of neurite migration) and the semaphorin receptor (mode of axon-dendrite locking). The inter-regulation between both pathways is mediated by the intracellular signaling factor Rap1. However, the mechanism of this interconnection is unknown.

This PhD project aims to elucidate the nature of this crosstalk using a bottom-up reconstitution of integrin, semaphorin and Rap1 by developing a cell-surface mimicking membrane system. We aim to establish a functional membrane system that allows us to control the two modes, i.e. attachment/detachment of two neighboring membranes representing dendrite and axon connections. The uniqueness of the project lies in the exact control of communication through membranes by the bottom-up strategy, which would be otherwise extremely challenging to elucidate. Moreover, the system will allow us to probe receptor interactions using biophysical, light microscopic as well as cryo-EM methods to understand the underlying principles of neural network formation and neuronal regeneration.

Our collaborative team has expertise in a wide variety of interdisciplinary techniques to facilitate the proposed PhD research, such as X-ray crystallography, cryo-EM, biophysical analysis, membrane biology and light microscopy. Mizuno lab is leading in the use of cryo-EM in combination with cellular methods to visualize cell shape formations controlled by the integrin signaling pathway and the remodeling of cytoskeleton components. Jones lab has a long-standing interest in axon guidance and structural biology of membrane proteins. Yvonne Jones co-heads the Structural Biology Division of the Wellcome Centre for Human Genetics at the University of Oxford.

This project will give a candidate a tremendous opportunity to apply cutting-edge in vitro reconstitution methods in the field of structural- and neuro- biology.

NIH Mentor: Dr. Naoko Mizuno (NHLBI)
UK Mentor: Prof. Andrew Carter

University: Cambridge, Laboratory of Molecular Biology (LMB)
Project listed date: September 2019
Project:

Neurons are specially shaped cells that have an extremely polarized structure. They contain protrusions called dendrites and a long axon extending from cell body that connect to neighbouring cells forming a neural network. Axons and dendrites retain a dynamic plasticity throughout the whole lifespan of a neuron to ensure the ability to adjust and adapt neural network connections.  The polarity and plasticity of neurons is maintained by a cytoskeleton of actin filaments and microtubules together with associated motors and other essential proteins. 

This PhD project aims to elucidate the molecular organization of axons and dendrites using in situ cryo-electron tomography (cryo-ET) of primary neurons.  We will address how cytoskeletal filaments and motors drive the branching, elongation and neural network formation. To this end we form a strong collaboration between the lab of Andrew Carter at the Laboratory of Molecular Biology (LMB), Cambridge University and Mizuno Naoko at the National Heart, Lung and Blood Institute at NIH. Mizuno’s lab’s expertise is visualizing cell shape formations controlled by remodelling of cytoskeleton and the Carter lab has a long-standing interest in how trafficking is carried out by cytoskeletal motors.

Cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) bridge the resolution gap between light-microscopy and conventional structural methods for gaining information on a molecular level (X-ray crystallography/NMR).  Current technical developments further facilitate in-depth analysis of cells on a molecular level that has not been possible before. The skillset obtained in this PhD project will be highly relevant to the field of newly emerging structural cell biology.

NIH Mentor: Dr. James R. Sellers (NHLBI)
UK Mentor: Prof. Philipp Kukura
University: Oxford, Department of Chemistry
Project listed date: September 2019
Project: This project would be to extend a long standing and productive collaboration between the Kukura lab at Oxford and the Sellers lab at NIH.  The specialty of the Kukura lab is in the development of light microscopic approaches to study novel biological processes with high temporal and spatial resolution.  The strength of the Sellers lab is in the production and characterization of myosins using various biochemical and biophysical approaches.

NIH mentor: Dr. Chris Hourigan (NHLBI)
UK mentor: Prof. Chris O'Callaghan
University: Oxford, Nuffield Department of Medicine

Project listed date: October 2020
Project: It is well recognized that acquired genetic mutations are an important cause of cancer, but recent studies have suggested that such somatic mutations are also associated with atherosclerosis. Somatic mutations have been found in blood from 10% of people over 70 years of age and 20% of people over 90 years of age and appear associated with an increased risk of atherosclerotic disease. Although age is a known independent risk factor for atherosclerosis, the basis for this has not been known.  It now appears likely that these mutations, several of which are found in genes known to regulate inflammation and immunity, are either a direct contributor to, or a potential biomarker for, this age-associated risk. The challenge now is to identify molecular mechanisms linking these somatic mutations with atherosclerosis.

This PhD project will investigate the cellular and molecular basis of the association between age associated DNA mutations and atherosclerotic disease risk. To do this will require cross-disciplinary collaboration, so this project brings together two highly complementary groups to address this important new biomedical challenge. At the National Heart, Lung and Blood Institute of the NIH, Chris Hourigan works on these acquired mutations in the context of a blood cancer called acute myeloid leukemia. At Oxford, Chris O’Callaghan works on molecular mechanisms involved in atherosclerosis and the genetic control of those mechanisms, especially in vessel wall inflammation.

This is a very exciting new field and has potential to identify new drug targets and so benefit patients with atherosclerosis. The experience gained by this doctorate will be highly relevant to other fields and will include cellular and molecular biology, high throughput sequencing approaches including single cell approaches and analysis of genetic variation.

NIH Mentor: Dr. Claudia Kemper (NHLBI)
UK Mentor: Dr. Menna Clatworthy
University: Cambridge, Department of Medicine
Project listed date: September 2019
Project: Dissecting the role of the complosome in immune cell tissue residency

Intracellular complement (the complosome) emerges as key regulator of key cell metabolic pathways in a range of (immune) cells. In consequence, perturbations in complosome activity contribute to human disease states, including recurrent infections and autoimmunity. Recent data also indicate that high complosome expression is the defining feature of tissue-resident immune cells including T cells and macrophages. In this project, we will combine pertinent mouse models and intravital imaging to address the role of the complosome in maintaining residency and sustaining function crosstalk between immune and parenchymal cells in tissues (lung/kidney/brain?) during normal homeostasis and in disease (which one?).

NIH Mentor: Dr. Ken Olivier (NHLBI) & Dr. Steve Holland (NIAID) 
UK Mentor: Prof. Andres Floto
University: CambridgeDepartment of Medicine
Project listed date: October 2020
Project: Forward and reverse genetic screening of macrophages and epithelial cells to identify host factors controlling nontuberculous mycobacterial infection.

NIH mentor: Dr. Antonina Roll-Mecak (NHLBI / NINDS)
UK mentor: Prof. Philipp Kukura
University: Oxford, Department of Chemistry
Project listed date: September 2019
Project: The tubulin code in health and disease

NIH mentor: Dr. Justin Taraska (NHLBI)
UK mentor: Dr. Sean Munro
University: Cambridge, MRC Lab of Molecular Biology
Project listed date: September 2019
Project: Develop and apply new super-resolution fluorescence and electron microscopy methods to the study of membrane traffic.

NIH Mentor: Dr. Michael N. Sack (NHLBI)
UK Mentor: Dr. Frances M. Platt
University: Oxford, Biochemistry and Pharmacology
Project listed date: October 2019
Project: The nutrient sensing and quality control linked organelles called lysosomes are best known to immunologists due to their roles in antigen presentation (dendritic cells) and in the facilitation of pathogen elimination (macrophages). Their role in the control of immunity is further recognized that inhibition of lysosomal function can promote anti-inflammatory effects by preventing the degradation of glucocorticoid receptors and conversely that impaired lysosome function in genetic lysosome storage diseases can blunt the number and function of natural killer cells. The Platt laboratory (Dept. of Pharmacology, Univ. of Oxford) investigates immune function in lysosome storage disease and the Sack laboratory (NHLBI, NIH) explores the molecular machinery controlling lysosomal homeostasis and their roles in immunity. An integrated project between the two labs, in collaboration with an NIH OxCam Scholar would be designed to enable the pursuit of an Ph.D. studying the role of lysosomes in controlling immune function.
 

National Human Genome Research Institute (NHGRI)

NIH mentor: Dr. Philip Shaw (NHGRI)
UK mentor: Collaborators at both universities
University:
Project listed date: September 2019
Project: Interplays between genome, the epigenome and the environment in shaping the development of brain and behavior.

National Institute on Aging (NIA)

 

National Institute of Allergy and Infectious Diseases (NIAID)

NIH mentor: Dr. Leah Katzelnick (NIAID)
UK mentor: 
University:
Project listed date: October 2020
Project: A previous infection with one of the four dengue viruses increases future risk of severe dengue disease, including hemorrhagic fever, upon infection with a different dengue virus. For this reason, dengue viruses 1-4 are challenging vaccine targets because sub-protective vaccines can increase risk the disease vaccines are designed to prevent. In the Viral Epidemiology and Immunity Unit (Chief, Dr. Katzelnick), we aim to identify correlates of natural and vaccine protection and antibody-dependent enhancement in order to develop better next generation vaccines, extend the longevity of vaccine-induced immunity, and characterize how vaccines may affect viral evolution and transmission.  Our work combines immunology,
virology, and epidemiology, including close collaborations with research teams leading longitudinal cohort and vaccine studies in Nicaragua, Sri Lanka, Thailand, Ecuador, the Philippines, and other sites. Specific projects include studying quaternary ‘super-antibodies', which bind epitopes across viral envelope proteins, and testing whether these antibodies provide enduring protection against dengue and other viral diseases. We will also study antigenic evolution away from existing immunity for flaviviruses and coronaviruses. Dr. Katzelnick was part of the NIH OxCam program (2012-2016) and is open to collaborating with research groups at both Oxford and Cambridge to mentor Ph.D. students.

NIH mentor: Dr. Joshua Tan (NIAID)
UK mentor:  Prof. Matthew Higgins
University: Oxford, Department of Biochemistry
Project listed date: October 2020
Project: Monoclonal antibodies have emerged in recent years as powerful tools to guide vaccine design and potentially to directly prevent infectious disease. Plasmodium falciparum, which causes malaria, is a relatively unexplored pathogen in this area, with only a few major vaccine candidates dominating the field despite the thousands of proteins expressed by the parasite. This project aims to isolate, characterize and determine the structures of human monoclonal antibodies against known and novel P. falciparum blood-stage antigens using cutting-edge technology. This collaborative project combines the expertise of the Tan lab in isolating human monoclonal antibodies against infectious pathogens and the expertise of the Higgins lab in solving crystal structures of antibody-antigen complexes to identify new sites of vulnerability on parasites at high resolution.
 

NIH mentor: Dr. Stefan Muljo (NIAID)
UK mentor: Dr. Anindita Roy 
University: Oxford, Department of Paediatrics
Project listed date: August 2020
Project: Elucidating fetal haematopoiesis in mouse and human

Hematopoiesis is a finely tuned process by which mature blood cells of multiple lineages are constantly generated throughout life from hematopoietic stem cells. In humans, definitive hematopoiesis commences in the fetal liver (FL) at around five weeks of gestation, and remains the main site of hematopoiesis throughout fetal life. Hematopoiesis in the bone marrow (BM) starts around 11-12 weeks of gestation, but does not take over as the primary site of hematopoiesis until just after birth. Recent evidence suggests that fetal hematopoiesis is distinct from postnatal hematopoiesis in many ways. Most of these studies have been done on mouse models, but whether these differences exist in, or are a true reflection of hematopoiesis in the human setting, remains to be determined. We, and others have begun to investigate unique features of human fetal hematopoiesis and this project will determine fetal specific programmes that change through ontogeny. This may depend on the physiological processes or demands of that particular developmental stage, and/or in response to specific microenvironmental cues. This research is clinically relevant since the transplantation of hematopoietic stem cells from donors of different ages vary in their regenerative and differentiation potential. Studying hematopoiesis throughout the human lifespan may be important not only to understand normal developmental processes, but also to understand the pathogenesis of postnatal haematological diseases that may have their origins in fetal life. Research by the Roy laboratory particularly focuses on properties of fetal cells that contribute to leukemia initiation in utero and how these might change after birth, and we have recently developed a unique infant acute lymphocytic leukemia (ALL) model. We are particularly interested in ‘oncofetal’ genes that might define the biology of infant and childhood leukemias; and whether they can be manipulated for therapeutic interventions. 

NIH Mentor: Dr. Sonja M. Best(NIAID)
UK Mentor: Dr. Julien Prudent (Cambridge)
University: Cambridge, MRC Mitochondrial Biology Unit
Project listed date: August 2020
Project: Elucidating the interplay between mitochondrial dynamics, membrane contacts sites and viral infection driving inflammation

The last decade has witnessed repeated emergence of RNA viruses with high pathogenic potential in humans including SARS-CoV-2, Zika virus, yellow fever virus and Ebola virus. The inflammatory response to infection is a major driver of pathogenesis, but the molecular mechanisms by which these viruses initiate and dysregulate inflammation are not well defined. Mitochondria are now recognized as critical regulators of the immune system and inflammation, serving as both signaling platforms and as sources of danger-associated molecular patterns (DAMPs) to initiate diverse signaling pathways. SARS-CoV-2, like other positive stranded RNA viruses, uses membranes derived from the ER for their replication factories, but also actively manipulates mitochondria, Golgi apparatus and other membrane bound organelles for replication purposes. However, it is unclear why mitochondria are hijacked during viral replication, and what the consequences of this manipulation are to inter-organelle communication and inflammation. This PhD project will use SARS-CoV-2 infection models in tissue culture and mouse models coupled to cutting-edge microscopy analysis to determine novel ways in which mitochondrial membrane remodelling and organelle contact sites are controlled, and the importance of these events as drivers of inflammation.

NIH Mentor: Dr. Clif Barry (NIAID)
UK Mentor: Dr. Helen McShane
University: Oxford, Immunology
Project listed date: September 2019
Project: Rational strategies for TB vaccine development
There is an urgent need for an improved TB vaccine. Advances in CRISPR/CAS technology in Mycobacterium tuberculosis have created the opportunity to rapidly evaluate novel knock-outs/knockdowns in this organism. With an improved understanding of the outer cell envelope of this deadly pathogen we aim to systematically construct and evaluate mutants in critical, highly exposed proteins present on the surface of Mtb cells to identify potential candidate vaccines that would be evaluated in cellular and animal models. This project has an overall goal of advancing both our understanding of the host immune response and the role of bacterial surface proteins in mycobacterial survival in vivo.

NIH mentor: Dr. Bibiana Bielekova (NIAID)
UK mentor:
University:

Project listed date: September 2019
Project: Development of cell-specific or process-specific biomarkers for CNS diseases.

NIH mentor: Dr. Sanjay Desai (NIAID)
UK mentor: Various collaborators at Oxford, Cambridge, and Wellcome Sanger, depending on project.
University: Oxford

Project listed date: September 2019
Project: Cellular and Molecular Biology of Malaria Parasites

Malaria remains an important global health problem; with increasing drug resistance and the lack of an effective vaccine, new therapies are needed and should be based on a rigorous understanding of parasite biology. Our NIAID lab has used a multidisciplinary approach to discover and characterize the three known ion channels in bloodstream malaria parasites. Through academic and pharmaceutical collaborations, we have also found potent inhibitors that are being pursued as new antimalarial drugs. Research projects will be tailored to the interests of the trainee and expertise available in possible collaborator labs. These projects may utilize molecular biology including CRISPR and heterologous expression, structural biology including cryoEM, biochemical methods including electrophysiology, epigenetics, and high-throughput screening for drug discovery.  These and other methods are actively used in the lab.

NIH Mentor: Dr. Raphaela Goldbach-Mansky (NIAID)
UK Mentor: Prof. Clare Bryant
University: Cambridge, Department of Veterinary Medicine

Project listed date: September 2019
Project: How do disease-inducing mutations affect inflammasome formation and activation?

NIH Mentor: Dr. Steve Holland (NIAID) / Dr. Adriana Marques (NIAID)
UK Mentor:
University:
Project listed date: September 2019
Project: Host response in Lyme disease: investigating factors associated with local control, dissemination and persistence.

NIH Mentor: Dr. Steve Holland (NIAID) & Dr. Ken Olivier (NHLBI)
UK Mentor: Prof. Andres Floto
University: CambridgeDepartment of Medicine
Project listed date: September 2019
Project: Forward and reverse genetic screening of macrophages and epithelial cells to identify host factors controlling nontuberculous mycobacterial infection.

NIH Mentor: Dr. Steve Holland (NIAID)
UK Mentor: Prof. Lalita Ramakrishnan
University: Cambridge, Department of Medicine
Project listed date: September 2019
Project: 

NIH mentor: Dr. Michael Lenardo (NIAID)
UK mentor: Prof. Christoph Hess 
University: Cambridge, Department of Medicine
Project listed date: September 2019
Project: The metabolic repertoire of immune cells – which encompasses metabolic enzymes/pathways, the available nutrient sensors and metabolic checkpoint kinases, and the epigenetic programming of metabolic genes – directly enables and modulates specific immune functions. Capitalizing on a large cohort of patients suffering from rare genetic immunodeficiency that have been whole-genome sequenced, our goal is to delineate the genetic and molecular basis of how cellular metabolism regulates immune-function in human health and disease states. Experimental approaches will involve genomics, molecular biology, cell biology, immunology, and biochemistry with an aim to elucidating mechanisms that lead to new treatment approaches to inborn diseases of immunity.

NIH Mentor: Dr. Vincent Munster (NIAID)
UK Mentor: Prof. Olivier Restif
University: Cambridge, Department of Veterinary Medicine
Project listed date: September 2019
Project: What makes bats good reservoirs of zoonotic viruses?

A growing number of emerging infectious diseases, often with high fatality rates, have been traced back to bats, one of the most diverse and still mysterious order of mammals. Together with Dr Munster, my group is part of an international consortium investigating the association between Henipaviruses and their bat hosts on three continents (https://www.bat1health.org/). This project will combine laboratory work in the NIH Laboratory of Virology with mathematical modelling and bioinformatics at the University of Cambridge. The goal will be to model the interactions between viruses and the immune system of bats, in order to understand the role of within-host dynamics in the maintenance and shedding of zoonotic viruses in bat populations. There may be opportunities to take part in field work in Africa too. Specific research and learning objectives will be tailored to the student’s profile and interests.

NIH Mentor: Dr. Aleksandra Nita-Lazar (NIAID)
UK Mentor: Prof. Clare Bryant
University: Cambridge, Department of Veterinary Medicine
Project listed date: September 2019
Project: Study of the PTM and protein expression dynamics in the Toll-like receptor pathway. Because dynamic PTMs such as phosphorylation, ubiquitination, or glycosylation are essential for the regulation of cell signaling, it is crucial to quantitatively map the PTMs of proteins involved in signaling cascades. We use the data to model the signaling network changes and their impact on innate immunity.

NIH Mentor: Dr. Aleksandra Nita-Lazar (NIAID)
UK Mentor: Dr. Michal Minczuk
University: Cambridge, MRC Mitochondrial Biology Unit 
Project listed date: September 2019
Project: Studies of the connection between metabolism and innate immunity using mitochondrial mouse mutant models and quantitative proteomics.

NIH Mentor: Dr. Susan Pierce (NIAID)
UK Mentor: 
University:
Project listed date: September 2019
Project:

NIH mentor: Dr. Thomas Quinn (NIAID)
UK mentor: Prof. Christophe Fraser
University: Oxford, Big Data Institute
Project listed date: September 2019
Project: Understanding HIV incidence at a population level is critical for monitoring the epidemic and understanding the impact of interventions. Using full length sequencing of HIV we are developing models for estimating incidence based on viral diversity which increases with time in the infected host. Using data from longitudinal cohorts we will develop these models and then apply them to large population based interventions to determine their impact.  Experimental approaches include next-generation sequencing, phylogenetic analysis, modelling and statistical methodologies.

NIH mentor: Dr. Thomas Quinn (NIAID)
UK mentor: Prof. Christophe Fraser & Prof. Katrina Lythgoe
University: Oxford, Big Data Institute
Project listed date: September 2019
Project: In this project you will use state-of-the-art viral sequencing data, combined with epidemiological data and mathematical modeling, to create an integrated understanding of HIV transmission. HIV places an enormous burden on global health. Implementing treatment and interventions can save millions of lives, but to do this effectively requires us to be able to predict the outcome of interventions, and to be able to accurately assess how well they are working once implemented. For HIV, these efforts are hampered by long durations of infections, and rapid within-host viral evolution during infection, meaning the virus an individual is infected with is unlikely to be the same as any viruses they go on to transmit.
 
For this project, you will identify individuals enrolled in the Rakai Community Cohort Project, based in Uganda, who are part of possible transmission chains, and for whom multiple blood samples are available throughout infection and at the time of transmission. These samples will be sequenced using state-of-the-art technology developed at the University of Oxford enabling the sequencing of thousands of whole virus genomes per sample, without the need to break the viral genomes into short fragments (whole-haplotype deep sequencing). Using this data, you will comprehensively characterize viral diversity during infection and at the point of transmission. Key questions you will tackle are:
 
- Do ‘founder-like’ viruses (similar to those that initiated infection) persist during chronic infection?
- Is there a consistent pattern of evolution towards population consensus virus?
- Are ‘founder-like’ viruses, or ‘consensus-like’ viruses more likely to be transmitted?
- Does the transmission of drug-resistant virus depend on the history of the transmitting partner?

NIH Mentor: Dr. David Sacks & Dr. Michael Grigg (NIAID)
UK Mentor: Prof. William James
University: Oxford, Dunn School of Pathology
Project listed date: September 2019
Project: Leishmaniasis is an important disease caused by protozoan parasites that are transmitted by infected sand fly bites in tropical and subtropical regions.  Depending on the strain of Leishmania, disease forms in humans range from localized, self-limiting cutaneous lesions to visceralizing infections that are fatal in the absence of treatment.   The specific contribution of parasite genotype to disease outcome remains largely unknown. Taking advantage of a recently revealed sexual cycle that occurs during Leishmania development in the insect vector, our goal is to generate a series of hybrids between cutaneous and visceral strains that will be phenotyped in mouse models of cutaneous and visceral leishmaniasis.  Each hybrid will be subjected to whole genome DNA and RNA-sequencing to follow parental allele, structural variation, including chromosome somy, gene expression, and epigenetic differences that associate with disease outcome.  Experimental approaches will involve genetic manipulation of the parasite, DNA and RNAseq analysis, single cell genomics, and the application of various computational/bioinformatics methods developed to facilitate QTL and GWAS studies that identify linkage between genes and phenotypes.  

NIH Mentor: Dr. Jonathan Yewdell (NIAID)
UK Mentor: Prof. Ervin Fodor
University: Oxford, Dunn School of Pathology
Project listed date: September 2019
Project: Study cell and molecular biology of influenza A virus replication.


NIH Mentor: Dr. Jonathan Yewdell (NIAID)
UK Mentor: Prof. Alain Townsend
University: Oxford, Weatherall Institute of Molecular Medicine
Project listed date: September 2019
Project: Influenza A virus imposes a significant socio-economic burden on humanity.  Vaccination is effective in only 60% of individuals, even under optimal circumstances.  The difficulty stems from the remarkable ability of influenza A virus to evade existing immunity.  IAV’s error prone polymerase enables the rapid antigenic evolution of the two virion surface glycoproteins, neuraminidase (NA) and hemagglutinin (HA).  Since the most potent antibodies (Abs) at neutralizing viral infectivity are directed the HA and NA globular domains, amino acid substitutions in these regions enable IAV to evade Ab-based immunity.  The project focuses on understanding the “immunodominance” of Ab responses to HA and NA in humans.  Immunodominance describes the strong tendency of the immune response to respond to complex antigens in a hierarchical manner, with higher ranking, “immunodominant” antigens potentially suppressing (“immunodominating”) responses to “subdominant” antigens.  By focusing responses on single antigenic sites, it is likely responsible for enabling influenza A virus to evade immunity by allowing the virus to sequentially alter its antigenicity.


NIH mentor: Dr. Jinfang (Jeff) Zhu (NIAID)
UK mentor:
University:
Project listed date: September 2019
Project: Understanding of the mechanisms through which CD4 T helper cells and innate lyphoid cells acquire their specific protective/tissue damaging effects.

NIH Mentor: Dr. Vincent Munster (NIAID)
UK Mentor: Prof. Teresa Lambe (also including Prof. Thomas Bowden & Prof. Sarah Gilbert)
University: Oxford, Nuffield Department of Medicine
Project listed date: October 2019
Project: Some of the most globally impactful diseases are caused by emerging and re-emerging viral pathogens. We have a long-standing collaboration with Vincent Munster at the NIH, investigating disease pathogenesis and developing vaccines against a number of outbreak pathogens.
 
This project represents an opportunity to join this world-class team to advance these works, investigating the mechanisms of disease, deriving correlates of protection, testing new therapeutic interventions and deriving structural determinants of disease through collaboration with Prof. Thomas Bowden.
 

National Institute of Child Health and Human Development (NICHD)

NIH Mentor: Dr. Tamas Balla (NICHD)
UK Mentor: Prof. Colin W Taylor
University: Cambridge, Department of Pharmacology
Project listed date: September 2019
Project: Close contacts between different membranes are important points of communication between intracellular membranes and between them and the plasma membrane. This project will use high-resolution optical microscopy and novel genetically encoded probes to examine the contribution of these membrane contact sites to spatially organized calcium and phospholipid signalling pathways.

NIH mentor: Dr. Stephen Kaler (NICHD)
UK mentor:
University:
Project listed date: September 2019
Project: Identifying genetic causes of neurometabolic disorders and develop gene therapy treatments for these diseases

NIH Mentor: Dr. Karel Pacak (NICHD)
UK Mentor: 
University: 
Project listed date: September 2019
Project: Undertake genomic and epigenomic studies into the mechanisms of tumorigenesis in individuals with inherited predisposition to neuroendocrine tumor syndromes, especially pheochromocytoma/paraganglioma associated with mutations in the Krebs cycle. Such discoveries can lead to understanding of developmental and other mechanisms in these tumors related to the same syndrome but behaving in a different way and occurring in different tissue of origin. Such data can be paramount to study novel therapeutic approaches for these tumors based on the discovery on novel tumor-specific targets as well as biomarkers.

NIH Mentor: Dr. Mihaela Serpe (NICHD)
UK Mentor: Prof. Matthias Landgraf
University: Cambridge, Department of Zoology
Project listed date: September 2019
Project: Regulation of neuronal plasticity – integration of synaptic signaling pathways

Neuronal plasticity is fundamental to nervous system development and function. We have recently discovered that reactive oxygen species (ROS), known for their destructive capacity in the ageing or diseased brain, function as second messengers for implementing structural plasticity at synaptic terminals. Moreover, different sources of ROS (cytoplasmic vs mitochondrially generated) regulate genetically distinct aspects of synapse development (growth vs release site number). Do ROS sculpt synapse plasticity in response to the metabolic state of neurons? How does ROS signaling intersect with other signaling pathways regulating synaptic plasticity, such as BMP and Wnt? This project will combine biochemical and genetic approaches with electrophysiology and methods for live and super-resolution imaging to investigate the contribution of various signaling pathways to synapse plasticity. We expect this project to redefine our understanding of how multiple signaling pathways integrate at the synapse to regulate distinct elements of plasticity.

NIH Mentor: Dr. Gisela Storz (NICHD)
UK Mentor: Prof. Ben Luisi
University: Cambridge, Department of Biochemistry
Project listed date: September 2019
Project: The project will use X-ray crystallography, cryoEM, microbial genetics and molecular biology to explore how small RNAs and small proteins act as regulators with speed and precision in diverse bacteria.

NIH mentor: Dr. Brant Weinstein (NICHD)
UK mentor:
University:
Project listed date: September 2019
Project: Organogenesis of the Zebrafish Vasculature.

NIH Mentor: Dr. Robert J. Crouch, (NICHD)
UK Mentor: Dr. Natalia Gromak
University: Oxford, Dunn School of Pathology
Project listed date: October 2019
Project: Unusual RNA/DNA structures (R-loops) are formed when the RNA hybridizes to a complementary DNA strand, displacing the other DNA strand in this process. R-loops are formed in all living organisms and play crucial roles in regulating gene expression, DNA and histone modifications, generation of antibody diversity, DNA replication and genome stability. R-loops are also implicated in human diseases, including neurodegeneration, cancer mitochondrial diseases and HIV-AIDs.
Collaboration between Prof Crouch (NIH) and Dr. Gromak (Oxford) labs will focus on understanding the regulation of R-loops and uncover the molecular mechanisms which lead to R-loop-associated diseases. We will employ state-of-the-art techniques including CRISPR, Mass Spectrometry and molecular biology approaches to understand the principles of R-loop biology in health and disease conditions. In the long term the findings from this project will be essential for the development of new therapeutic approaches for R-loop-associated disorders.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 

NIH Mentor: Dr. Yihong Ye (NIDDK)
UK Mentor: 
University: 
Project listed date: December 2020
Project: The goal of our research is to understand how cells use various protein quality control (PQC) strategies to eliminate misfolded proteins, and how defects in these processes lead to aging-associated neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Specifically, we study the molecular mechanisms underlying protein translocation-associated quality control at the endoplasmic reticulum (ER), the export of misfolded proteins via unconventional protein secretion, and cell-to-cell transmission of misfolded alpha-Synuclein and Tau aggregates. We envision that a thorough characterization of these protein quality control systems may one day improve both diagnosis and treatment of aging-associated neurodegenerative diseases.

NIH Mentor: Dr. Priyanka Naranka (NIDDK)
UK Mentor: 
University: 
Project listed date: December 2020
Project: Alzheimer’s disease is the most common neurodegenerative disease. It affects millions of individuals worldwide. Because of large scale genomic studies, we know a number of genetic risk factors that increase the risk for disease. We also know a few factors that promote resilience to disease onset. The Narayan lab seeks to identify, understand, and modulate the cellular pathways that underlie risk and resilience to Alzheimer’s disease.  We do this with the goal of developing new therapeutic or preventative strategies for neurodegenerative diseases. To accomplish our research goals, we use a combination of genetics, biochemistry, molecular biology, and human induced pluripotent stem cell (iPSC)-derived neuronal and glial cell types. We’re excited to welcome new team members interested in studying the cell biology behind neurodegenerative disease risk.

NIH Mentor: Dr. Astrid D. Haase, MD, PhD (NIDDK)
UK Mentor: Dr. Felipe Karam Teixeira, PhD (Cambridge)
University: Cambridge, Department of Genetics
Project listed date: November 2020
Project: Germline genomes are immortal.  Their genetic information is transmitted to the next generation and ensures that continuation of life.  To protect the integrity of their genomic information, germ cells employ a specialized small RNA-based defense system, PIWI-interacting small RNAs (piRNAs) and their PIWI protein partners.  The interest of the Karam Teixera lab in germ cell biology and evolution and the focus of the Haase lab on mechanisms of small silencing RNAs converge on piRNA-guided surveillance of genome integrity. The collaborative project of an OxCam Scholar is designed to combine strength of both labs in genetics, biochemistry and genomics, and offers training in experimental techniques and basic computational analyses of next-generation sequencing data.  Results from this graduate study will further our understanding of how germ cells ensure genome integrity and the survival of future generations. 

NIH Mentor: Dr. Michael Krashes (NIDDK)
UK Mentor:  Dr. David Dupret (MRC BNDU, NDCN)
University: Oxford, MRC Brain Network Dynamics Unit, Nuffield Department of Clinical neurosciences
Project listed date: October 2020
Project: Humans and animals adjust their feeding behaviour according to many environmental factors, including the spatial context where food is found and consumed. Such contextual control of food seeking and eating is notably central to the ability to meet future needs and maximise chances of survival to changes in feeding routines but their underpinning brain network mechanisms and pathways remain unclear. The Dupret laboratory (MRC Brain Network Dynamics Unit at the University of Oxford) investigates how the concerted spiking activity of neurons supports memory and the Krashes laboratory NIH/NIDDK) investigates homeostatic and non-homeostatic feeding behaviour. An integrated project between the two labs, in collaboration with an NIH OxCam Scholar would be designed to enable the pursuit of an Ph.D. revealing circuit mechanisms of contextual control of feeding behaviour using in vivo large-scale network recordings in behaving rodents, combined with optogenetic and closed-loop optogenetic manipulations.

NIH Mentor: Dr. Behdad (Ben) Afzali (NIDDK)
UK Mentor: Prof. Holm UhligDr. Arian Laurence
University: Oxford, Nuffield Department of Medicine
Project listed date: September 2019
Project: Investigating the role of transcription factor networks in T cell immunoregulatory fate decisions

Regulatory T cells expressing the FoxP3 transcription factor (Tregs) are arguably the most important naturally-occurring anti-inflammatory cells in the body and are prime candidates for cellular therapy of autoimmunity and transplant rejection. They are potently immunosuppressive, indispensable for maintaining self-tolerance and in resolving inflammation. Tregs can be induced to develop dichotomously from naïve precursors that also have the ability to differentiate into inflammatory T cell lineages. The choice of differentiation pathway (“fate decisions”) is directed by environmental signals and interplay between many transcription factors working within networks. The expression of many genes is required for a healthy immune response and this is highlighted by the discovery of many gene mutations that are associated with very early onset auto-immune disease.

Our goal is to understand how transcriptional signals from the environment are integrated in T cells to determine inflammatory versus regulatory T cell differentiation and the quality and duration of effector function. Experimental approaches will involve genomics of patients with primary immuno-deficiencies and very early onset colitis, next generation sequencing platforms (RNA-seq, ChIP-seq, Cut&Run, ATAC-seq, scRNAseq), molecular and cell biology, CRISPR genome editing and in vivo murine models.

NIH Mentor: Dr. Michael Krashes (NIDDK)
UK Mentor: Dr. Mark Evans
University: Cambridge, Department of Medicine
Project listed date: September 2019
Project: This project aims to determine how changes in blood glucose can affect hunger and the drive to feed and examine how this can be altered in conditions such as diabetes.

Hypoglycaemia (low blood glucose) is a complication of the treatment of diabetes with insulin. It is feared by people with diabetes and is associated with increased risk of death. One of the important defences against a falling blood glucose is the generation of hunger- a potent defence which both warns and directs towards corrective action to help restore blood glucose. A subset of people with diabetes develop defective defensive responses to and warning symptoms (including hunger) of hypoglycaemia. This puts them at a markedly increased risk of suffering severe episodes of hypoglycaemia.

We want to determine how hypoglycaemic feeding is triggered and the mechanisms by which this may become altered in diabetes. To examine this in murine models, we will combine the skills of Evans’ laboratory (hypoglycaemia, insulin clamp methodology, operant conditioning feeding assessment) located within the Institute of Metabolic Science with broader interest and expertise in appetite and feeding with Krashes’ laboratory (neurocircuitry of feeding) to examine how and where glucoprivic feeding maps onto both conventional feeding pathways and also the neurocircuitry which triggers other counter-regulatory responses to hypoglycaemia. The student will examine how this adapts after exposure to antecedent hypoglycaemia. Finally, they will examine potential therapeutic targets to boost/ restore or prevent the loss of protective hunger in diabetes with recurrent hypoglycaemia.

NIH mentor: Prof. Jake Liang (NIDDK)
UK mentor: Prof. Jane McKeating
University: Oxford, Nuffield Department of Medicine
Project listed date: September 2019
Project: Regulation of Hepatitis B Virus Infection by Hypoxic Signalling Pathways.

Viruses are obligate parasites that have evolved to manipulate their host to their advantage. Chronic viral infection of the liver is a global health problem, with over 300 million individuals infected with hepatitis B (HBV) or C (HCV) virus that causes liver disease which can progress to liver cancer. Viral hepatitis-related liver disease is the number 4 disease-related killer worldwide and is associated with more than 1 million deaths/year, highlighting an urgent need for new curative treatments. We recently discovered that low oxygen environments, naturally found in the liver, enhance HBV replication at several steps in the viral life cycle. Similar condition may apply to HCV replication. Cellular response to low oxygen is regulated by a family of oxygenases and hypoxia inducible factors (HIFs) that control genes involved in energy metabolism and other cellular processes. This project will study the role of hypoxic signaling and related metabolic pathways in HBV or HCV replication and their impact on pathogenesis, immune based and epigenetic therapies.

The successful candidate will investigate the molecular mechanisms underlying these observations. In particular, we will (i) identify the role of HIFs in HBV cccDNA biogenesis, transcription and metabolism, and production of infectious particles, and conduct comparative studies in HCV replication (ii) analyze how these host-virus interactions are shaped by the tissue microenvironment, genetic manipulations and metabolic parameters. The project has basic and translational research components and applies state-of-the-art technologies, tools and model systems to study HBV infection and its mechanism of disease. Taken together, this exciting project builds on strong preliminary results and existing expertise that may lead to new therapeutic targets and antiviral development.

NIH mentor: Dr. Brian Oliver (NIDDK)
UK mentor: Prof. Steve Russell (Cambridge) & Prof. Stephen Goodwin (Oxford)
University: Cambridge, Department of Genetics & Oxford, Department of Physiology, Anatomy and Genetics
Project listed date: September 2019
Project: Genomic and genetic basis of sex differences in development, physiology, and behavior.

NIH Mentor: Dr. Richard Proia (NIDDK)
UK Mentor: Prof. Francis Platt
University: Oxford, Pharmacology
Project listed date: December 2019
Project: Pathogenic mechanisms and novel therapies for lysosomal storage disorders and other neurodegenerative diseases

National Institute on Drug Abuse (NIDA)

NIH mentor: Dr. Lauren Atlas (NCCIH/NIDA)
UK mentor:
University:
Project listed date: September 2019
Project: Characterizing the psychological and neural mechanisms by which expectations and other cognitive and affective factors influence pain, emotional experience, and clinical outcomes.

National Institute of Environmental Health Sciences (NIEHS)

NIH Mentor: Dr. Guang Hu, (NIEHS)
UK Mentor:
University: 
Project listed date: December 2020
Project: Pluripotent stem cells, such as embryonic stem cells (ESCs), can be used as a model system to study the molecular basis of fate-specification during early mammalian development. They can also be used to derive various types of cells for disease modeling, drug discovery, regenerative medicine, and environmental health sciences. To fully realize these potentials of pluripotent stem cells, it is important to understand the molecular mechanisms that regulate the pluripotent state. We have previously carried out a genome-wide RNAi screen in mouse ESCs and identified a list of novel factors that are important for pluripotency maintenance. Among them, we are currently investigating the function of the Ccr4-Not mRNA deadenylase complex and the INO80 chromatin remodeling complex in ESCs, somatic cell reprogramming, and mouse development using biochemical, genetic, genomic and single cell analysis approaches. In addition, we are developing new genetic and genomic methods to identify and probe genes involved in stem cell fate specification. We are applying these methods in pluripotent and germline stem cells to better understand the maintenance, transition, resolution, and re-establishment of the pluripotent state.

NIH Mentor: Dr. Scott Auerbach, Dr. Nicole Kleinstreuer, & Dr. Nisha Sipes (NIEHS)
UK Mentor: Prof. Andreas Bender
University: Cambridge, Department of Chemistry
Project listed date: September 2019
Project: Combined Computational-Experimental Approaches to Predict Acute Systemic Toxicity.

NIH Mentor: Dr. Guohong Cui, (NIEHS)
UK Mentor: Prof. Armin Lak
University: Oxford, Department of Physiology, Anatomy & Genetics
Project listed date: October 2019
Project: Projection-specific signals of dopamine neurons in health and Parkinson’s disease

Midbrain dopamine neurons have fundamental roles in reward learning and movement control, and their dysfunction is associated with various disorders in particular Parkinson’s disease. Recent studies have shown substantial diversity in the activity of these neurons depending on where in the striatum their axons project. In our recent experiments we recorded the activity of dopamine axonal terminals while systematically manipulating stimuli, actions and rewards in a precise behavioural task. While the activity of dopamine projections to ventral regions of striatum mainly reflected rewards, dopamine axonal projections to dorsal striatum encoded contralateral stimuli and actions with negligible representation of reward value. These findings raise the questions of whether dopamine signals across striatum encode specific aspects of associations between stimuli, actions and rewards during learning, and whether these anatomically-specific dopamine signals are impaired during Parkinson’s disease. This project will address these questions using a combination of imaging, computational and behavioural experiments in healthy mice as well as mouse models of Parkinson’s disease. In Oxford University (Lak lab), we will use recent genetically–encoded dopamine sensors in combination with fiber photometry to monitor the dynamics of dopamine signals across the striatum while healthy mice perform a learning task guided by sensory stimuli and rewards. These results will provide a foundation for examining these dopamine signals during Parkinson’s disease, which will be performed at NIH (Cui lab). Using MitoPark mouse line (with progressive and robust phynotype of Parkinson’s disease), we will examine the dynamics of striatal dopamine signals using photometry during learning tasks established in healthy mice in Oxford. In analysing the data, we will use learning models to relate dopamine signals with normative computational models of decision making and learning. The project is primarily experimental in nature but will provide an opportunity to develop computational skills. The project will provide fundamental insights into behaviourally-relevant computations that dopamine signals across the striatum encode, and will uncover how these neuronal computations change during Parkinson’s disease. For further information visit: https://www.niehs.nih.gov/research/atniehs/labs/ln/pi/iv/index.cfm and www.laklab.org

National Institute of Mental Health (NIMH)

NIH mentor: Dr. Argyris Stringaris (NIMH)
UK mentor: Prof. Catherine Harmer (Oxford)
University: Oxford, Department of Psychiatry
Project listed date: August 2020
Project: Use experimental medicine and neuroimaging approaches to uncover the mechanisms mood disorders in adolescents and adults. Depression is a leading cause of burden of disease worldwide yet we know little about its pathogenesis. The student is going to work across the NIMH and Oxford laboratories and use neuroimaging (fMRI, EEG and MEG) in patients and controls who undergo experimental treatments.

NIH mentor: Dr. Armin Raznahan (NIMH)
UK mentor: Prof. Jason Lerch (Oxford)
University: Oxford, Wellcome Integrative Neuroimaging Center
Project listed date: September 2019
Project: “Translational Neuroimaging and Genomics of Sex Differences in Brain Development”

Humans display robust age-dependent sex differences in diverse domains of motor, language and social development, as well as in risk for developmentally-emergent disorders. There is a robust male-bias in risk for early-emerging impairments of attention, motor control, language and social functioning, vs. a female-bias for adolescent-emergent disorders of mood and eating behaviors.  The stereotyped pattern of these sex biases suggests a role for sex differences in brain development, and further implies that these differences unfold in a spatiotemporally-specific manner. In support of this notion - in vivo structural neuroimaging studies find focal sex differences in brain anatomy that vary over development. However, the mechanisms driving these neurodevelopmental differences remain poorly understood in humans. In particular, we do not know how specific spatial and temporal instances of sex-biased brain development in humans relate to the two foundational biological differences between males and females: gonadal sex-steroid profile (henceforth “gonadal”) and X/Y-chromosome count [henceforth “sex chromosome dosage” (SCD)]. In our prior cross-sectional neuroimaging studies, we have however provided extensive evidence that gonads and SCD can both shape regional anatomy of the human brain, and that similar effects can be observed in mice. However, to date there are no available data on the temporal unfolding of gonadal and SCD effects on regional brain anatomy, and no quantitative frameworks for comparing these effects between observational humans studies and experimental work in mice.

This project will build on a longstanding productive collaboration between Drs. Lerch and Raznahan, with rich existing datasets, to better-specify sex as a neurobiological variable in health and disease. Key questions for the project relate to (i) fine-grained spatiotemporal mapping of sex, SCD and gonadal effects using neuroimaging in transgenic mice and rare patient groups, (ii) computational solutions for comparison of these maps between species, and (iii) “decoding” of imaging data using measures of gene expression in brain tissue and integrative functional genomics. The resulting anatomical, and genomic signatures for sex-biased development will be probed for association with biological bases of sex-biased brain disorders.

NIH mentor: Dr. Armin Raznahan (NIMH)
UK mentor: Prof. Edward Bullmore / Dr. Petra Vertes (Cambridge)
University: Cambridge, Department of Psychiatry
Project listed date: September 2019
Project: Training opportunities: neuroimaging, genetics, transcriptomics, network science, developmental neuroscience, biology of mental disorders
Project details: The current project will build on our prior work in one of 2 broad directions and will be tailored based on the incoming student’s scientific and training goals:

1. Innovative methods for brain network mapping, and large-scale applications to population and clinical neuroscience. This could include, for example:
• Developing new methods to combine sMRI with additional in vivo imaging modalities (e.g. resting-state functional MRI).
• Applying new or existing methods could to characterize interindividual variation in brain organization and link this variation to behaviour and psychiatric risk.

2. Novel methods for cross-species or multi-scale data integration. This could include, for example:
• Developing next-generation neuroinformatic tools for linking between MRI connectomics, micro-scale (transcriptional, histological) data, and basic neuroscience studies at 7T (human) or 9.4T (animal)
• Using network-based models of the human brain from multiple data modalities to build predictive models of selective brain vulnerability to neuropsychiatric disease.
• Large-scale (n>20k) integrative applications, with a focus on linking MRI phenotypes in health and disease to genetics (array and sequencing-based data) and transcriptomics (brain atlases, post mortem data).

National Institute of Neurological Disorders and Stroke (NINDS)

NIH Mentor: Dr. Craig Blackstone (NINDS)
UK Mentor: Prof. Stefan Marciniak
University: Cambridge, Cambridge Institute for Medical Research 
Project listed date: September 2019
Project: A pathogenic mutant of α1-antitrypsin (Z-α1-antitrypsin) accumulates in the endoplasmic reticulum (ER), disrupting the ER’s tubular structure and interconnectivity as well as increasing the cell’s sensitivity to ER stress.  The efficiency of protein folding, which defends against ER stress, is dependent on diffusion at the nanoscopic scale.  Both folding and diffusion will are affected by ER structure and by the biophysical properties of its luminal environment, such as macromolecular crowding and microviscosity. We have developed Rotor-based Organelle Viscosity Imaging (ROVI) to allow real-time measurement of microviscosity in live cells and have found that Z-α1-antitrypsin forms a hydrogel in the ER that increases local microviscosity while reducing crowding.  This project will investigate chaperone mobility in Z‑α1‑antitrypsin expressing cells and elucidate the mechanisms linking hydrogel formation with increased sensitivity to ER stress, while using advanced super-resolution imaging approaches to assess changes in ER structure.

NIH Mentor: Dr. Carsten Bӧnnemann (NINDS)
UK Mentor: Prof. Rita Horvath
University: Cambridge, Department of Clinical Neurosciences
Project listed date: September 2019
Project: The aim of this project is to convert iNPCs of patients with different exosome component mutations into motor neurons, astrocytes and oligodendrioglia cells and perform functional and molecular studies exploring the effect of the mutations on RNA metabolism in these cells, which are predominantly affected in patients.

NIH mentor: Dr. Kenneth Fischbeck (NINDS)
UK mentor: Prof. Kevin Talbot and Prof. Dame Kay Davies
University: Oxford
Project listed date: September 2019
Project: Understand the disease mechanisms and potential treatments for hereditary motor neuron diseases such as spinal muscular atrophy and polyglutamine expansion diseases such as Huntington's disease.

NIH mentor: Dr. Avindra Nath (NINDS)
UK mentor:  Prof. Peijun Zhang
University: Oxford, Nuffield Department of Clinical Medicine
Project listed date: September 2019
Project: Determining the role of endogenous retroviruses in the pathophysiology of neurological diseases.

Retroviral sequences remain dormant in the human genome and occupy nearly 7-8% of the genomic sequence. We have shown that one of these viruses termed HERV-K (HML-2) is activated in patients with amyotrophic lateral sclerosis (ALS), and transgenic animals that express the envelope protein of HERV-K develop ALS like symptoms. Hence, we are now using a wide variety of structural biology and virology tools to determine the mechanism by which its expression is regulated and causes neurotoxicity to motor neurons. 

NIH mentor: Dr. Daniel Reich (NINDS)
UK mentor: Prof. Robin Franklin
University: Cambridge, Department of Clinical Neuroscience
Project listed date: September 2019
Project: Examine the dynamics of oligodendrocyte lineage cells in murine and primate models of multiple sclerosis using a combination of imaging, histopathological, and molecular techniques.

NIH mentor: Dr. Antonina Roll-Mecak (NINDS / NHLBI)
UK mentor: Prof. Philipp Kukura
University: Oxford, Department of Chemistry
Project listed date: September 2019
Project: The tubulin code in health and disease

NIH mentor: Dr. Kareem Zaghloul (NINDS)
UK mentor:
University:
Project listed date: September 2019
Project: Our lab seeks to explore the neural mechanisms underlying cognitive function by exploiting the unique investigative opportunities provided by intracranial electrical recordings during neurosurgical procedures. Using recordings captured from epilepsy patients implanted with subdural and depth electrodes, we investigate the activation of cortical networks during memory encoding and recall. And using recordings captured during implantation of deep brain stimulators, we investigate the role of the basal ganglia in learning and decision-making.

National Library of Medicine (NLM)

NIH mentor: Dr. Stefan Jaeger (NLM)
UK mentor: Prof. Richard Maude
University: Oxford, Nuffield Department of Medicine
Project listed date: August 2020
Project: Smartphone based image analysis for malaria diagnosis

Malaria is a major burden on global health with about 200 million cases worldwide, and 600,000 deaths per year. Inadequate diagnostics is a major barrier to effective management of cases and elimination of the disease. The current gold standard method for malaria diagnosis is light microscopy of blood films. About 170 million blood films are examined every year for malaria, which involves manually identifying and counting parasites. However, microscopic diagnostics are not standardized and depend heavily on the experience and skill of the microscopist, many of whom work in isolation, with no rigorous system in place for maintenance of their skills. For false negative cases this leads to incorrect diagnosis with unnecessary use of antibiotics, a second consultation, lost days of work, and in some cases progression into severe malaria. For false positive cases, this results in unnecessary use of antimalarial drugs and side effects.

To improve malaria diagnostics, the Lister Hill National Center for Biomedical Communications, an R&D division of the U.S. National Library of Medicine, NIH and Mahidol-Oxford Tropical Medicine Research Unit, University of Oxford, in Bangkok, Thailand are developing a fully automated low-cost system that uses a mobile phone and standard light microscope for parasite detection and counting on blood films. Compared to manual counting, automatic parasite counting is more reliable and standardized, reduces the workload of the malaria field workers and reduces diagnostic costs. To count parasites automatically, the system uses image processing methods to find cells infected with parasites in digitized images of blood films. The system is trained on manually annotated images and machine learning methods then discriminate between infected and uninfected cells, detect the type of parasites that are present, and perform the counting. The system uses a regular smartphone and digital images acquired on standard light microscopy equipment making it ideal for resource-poor settings.

This PhD project will develop and test this system for real-world use for malaria diagnosis. It will include optimisation of the system at NIH and testing of the system in the field at MORU including the smartphone application interface and performance, the system for connecting the smartphone to standard light microscopes, development of a core set of performance metrics for the application, field testing of the entire system for malaria diagnosis together with government healthcare workers and National Malaria Control Programme staff, structured interviews to gather feedback on the system and its potential role in malaria diagnosis in different settings, a formal field trial of the system performance and development of a system implementation guidance document for National Malaria Control Programmes.

The student will join a dynamic team of image analysis specialists at NLM and epidemiologists, modellers and clinicians at the MORU offices in Bangkok. They will spend time at field sites in malaria-endemic areas and will interact with government staff. Training will be provided at NIH on basic image analysis and smartphone application development and at MORU on malaria miscroscopy, clinical study methodology, data analysis and research ethics.

Oxford

UK Mentor: Dr. Hashem Koohy
University:  Oxford, Radcliffe Dept. Of Medicine
NIH Mentor:
Project listed date: November 2020
Project: Exploring mechanisms underlying heterogeneity of response in personalized cancer immunotherapy by using machine-learning techniques
T cell recognition of a cognate peptide-MHC (pMHC) complex presented by infected/malignant antigen-presenting cells are of utmost importance for mediating a robust and long-term immune response. The recognition is mediated by specific molecular interactions between heterodimeric T Cell Receptors (TCRs) and pMHC ligands and instructs the nature of ensuing adaptive immune response. A better understanding of TCR:pMHC interaction would allow further harnessing of the adaptive T cell immunity and may lead to the development of  vaccines and therapeutics  both in the context of personalized cancer immunotherapies and infectious diseases such as COVID19. The research interests in the Koohy group are focused on the development of machine-learning and Bayesian statistical models to help us better understand two key components of this interaction: A) architecture of the immune repertoire and its dynamics upon exposure to antigens, B) processing and presentation of antigens by MHC molecules to their cognate T cells.

Cancer is usually characterized by accumulation of genetic alterations. Tumour-specific somatic mutations may generate small mutated proteins known as neoantigens that are presented on the surface of cancer cell as ‘cancerous flags’ in association with class I and II HLA molecules.  Neoantigens can be recognized by autologous T cells as foreign and therefore are considered as targets for improved cancer vaccines and adaptive T cell therapies. Almost similar mechanisms are applied to infectious diseases with the difference that the immunogenic epitopes on the surface of infected cells originate from invasive pathogens. Prediction of both immunogenic viral epitopes and cancer neoantigens has been at the centre of extensive research around the globe over the past couple of decades but remains unsolved.   We have been developing various statistical models such as Bayesian Hidden Markov Models to predict immunogenic epitopes that can be used as targets for vaccines for personalized cancer immunotherapy as well as infectious diseases such as COVID1,2.

Over the past decade we have witnessed unprecedented achievements on various cancer immunotherapies in which patients’ own immune system is modulated to find and kill cancer cells. This is evident by the 2018 Nobel Prize for development of Immune Checkpoint Blocked ICB that has greatly improved patients care. However, not all patients respond the same way, besides, some patients develop immune related adverse events such as checkpoint colitis. 
Multiple factors affect immune response to treatment including mutation burden rate, cytotoxic T cell infiltration, antigen processing and presentation defects, mutation-driven clonal signature and the composition of intestinal microbiota. Owing to advances in high throughput sequencing technologies, in particular recent single cell advancements, these features can now be measured from patients’ samples at single cell level at multiple time points including before, during and after the treatment.  We take readouts of these experiments in the form of high throughput sequencing data including genomics, transcriptomics, T cell receptor repertoire, and epigenomics data to train  statistical and machine learning models to study the mechanisms underlying heterogeneity of the response.

UK Mentor: Prof. Kilian Huber
University:  Oxford, Centre for Medicines Discovery
NIH Mentor: Prof. Jordan Meier (NCI)
Project listed date: November 2020
Project: Chemical biology tools to study crosstalk between cell metabolism and protein degradation

In order to maintain homeostasis in response to environmental changes such as nutrient availability, eukaryotic cells have evolved intricate mechanisms to quickly increase or decrease the activity of fundamental processes such as gene expression, protein expression and degradation. Indeed, several metabolites act as cofactors for important cellular enzymes that regulate e.g. chromatin state and serve as templates for posttranslational modifications flagging proteins for proteolysis via the ubiquitin-proteasome system. Consequently, the identification of metabolites and complementary binding domains has broadened our understanding of human physiology and contributed to the development of new medicines to treat malignant and inflammatory disease. The aim of this project is to systematically map protein-metabolite interactions on a proteome-wide scale by combining the development of specific metabolite-inspired affinity reagents with unbiased approaches such as thermal profiling to dissect metabolite signalling in the context of protein degradation pathways in various cell types. Applicants will have the opportunity to take advantage of a unique combination of synthetic organic chemistry and cell biology techniques to identify new potential drug targets and develop first-in-class ligands for key regulators of protein homeostasis.

UK Mentor: Prof. Richard Bryant, Prof. Ian Mills, Prof. Jens Rittscher
University:  Oxford, Nuffield Department of Surgical Sciences; Institute of Biomedical Engineering, Department of Engineering Science,Big Data Institute, Nuffield Department of Medicine,
NIH Mentor: Dr. David Wink & Dr. Stephen Lockett (NCI)
Project listed date: November 2020
Project: Tissue multiplexing is a new imaging method that allows to visualise a large number of protein targets in tissues. This exciting new technology allows for new approaches to phenotyping cells and to decode more complex patters of communication between different tissue compartments. The goal of this project is to develop the required image analysis and inference methods using advanced machine learning and AI in 2D and 3D. As a result, you will be advancing our understanding of the tumour environment and find novel ways of identifying sub-populations of cells that play a critical role in disease progression.

You will be working side by side with world leading cancer researchers at NIH NCI and the University of Oxford. At both sites you will have access to unique patient cohorts. Together with David Wink and Stephen Lockett (both NCI) you will be working on aspects if breast cancer. In Oxford, Richard Bryant and Ian Mills will lead on work in prostate cancer, which is the commonest non-cutaneous cancer in men, and often progresses to incurable metastatic disease. Your work will also be supported by expert pathologists and you will be working towards improving current practice in cellular pathology.

The broader group has already established a very active collaboration and you will be expected to work in both locations. In Oxford, you will be embedded in the Quantitative Biomedical Image Analysis group led by Prof. Rittscher. Part of your role will be to accelerate the exchange of technology and software between the two locations. This project provides a unique opportunity to study mechanisms that are common to different cancer types.

UK Mentor: Prof. Holm Uhlig
University:  Oxford, NDM, Translational Gastroenterology Unit
NIH Mentor:
Project listed date: November 2020
Project: Inflammatory bowel disease (IBD) encompasses two major diseases Crohn’s disease and ulcerative colitis. A subgroup of patients develop extreme phenotypes of intestinal inflammation due to rare monogenic defects. This includes several forms of immunodeficiency with diverse functional pathogenic mechanisms. Those defects inform on the importance of antimicrobial activity, hyperinflammatory responses and immune regulation. We investigate children with very early onset of intestinal inflammation using whole genome or whole exome sequencing to discover novel high impact genes and analyse the involved signaling pathways in vitro, in situ and in vivo. We like to understand the pathogenesis of rare “orphan” diseases to develop better treatment options for those disorders and improve understanding of pathogenic mechanisms of IBD as a whole.
The project will focus on single cell proteomic and transcriptomic analysis of patients with monogenic forms of IBD in order to understand functional mechanisms of monogenic IBD, to understand cellular communication and to identify novel therapeutic targets to induce cellular antimicrobial activity in order to maintain and reinstall intestinal mucosal barrier function.

Aschenbrenner D, et al.  Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance. Gut. 2020 Oct 9:gutjnl-2020-321731. doi: 10.1136/gutjnl-2020-321731. Online ahead of print.

Serra EG, et al. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.
Nat Commun. 2020 Feb 21;11(1):995. doi: 10.1038/s41467-019-14275-y

Schulthess J, Pandey S, et al. The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages. Immunity. 2019 Feb 19;50(2):432-445.e7.

Uhlig HH, Powrie F. Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease. Annu Rev Immunol. 2018 Apr 26;36:755-781

UK Mentor: Prof. Kilian Huber
University:  Oxford, National Cancer Institute-Frederick, Chemical Biology Laboratory
NIH Mentor: Dr. Jordan Meier
Project listed date: November 2020
Project: In order to maintain homeostasis in response to environmental changes such as nutrient availability, eukaryotic cells have evolved intricate mechanisms to quickly increase or decrease the activity of fundamental processes such as gene expression, protein expression and degradation. Indeed, several metabolites act as cofactors for important cellular enzymes that regulate e.g. chromatin state and serve as templates for posttranslational modifications flagging proteins for proteolysis via the ubiquitin-proteasome system. Consequently, the identification of metabolites and complementary binding domains has broadened our understanding of human physiology and contributed to the development of new medicines to treat malignant and inflammatory disease. The aim of this project is to systematically map protein-metabolite interactions on a proteome-wide scale by combining the development of specific metabolite-inspired affinity reagents with unbiased approaches such as thermal profiling to dissect metabolite signalling in the context of protein degradation pathways in various cell types. Applicants will have the opportunity to take advantage of a unique combination of synthetic organic chemistry and cell biology techniques to identify new potential drug targets and develop first-in-class ligands for key regulators of protein homeostasis.

UK Mentor: Prof. Paresh Vyas
University:  Oxford, RDM
NIH Mentor: Dr. Chris Hourigan (NHBLI)
Project listed date: November 2020
Project: Acute Myeloid Leukaemia (AML) is the most common, aggressive human leukemia. Within the whole group of AML patients there is a subset of patients, typically younger (less than 65 years of age) who receive intensive conventional combination cytotoxic chemotherapy (anthracyclines and nucleoside analogues), who have a higher cure rate (~65%)[3]. Despite these cytotoxic drugs being in routine clinical use since the 1970’s, the field surprisingly still does not understand why these patients are cured. Conventional wisdom is that these patients are cured, because intensive combination cytotoxic chemotherapy kills all AML cells. However, this has never been rigorously proven and alternative hypotheses have not been tested.
This proposal will test if in patients who are cured, compared to those who are not, if eradication of all AML cells, could result from:
1. Increased killing of AML from cytotoxic chemotherapy.
2. An autologous innate and, or, acquired immune anti-AML cell response.
3. A combination of (1) and (2).
Specific Aims:
Using patient samples from cured patients and patients who relapse we will:
1. Contrast amount of AML cells left after treatment (measurable residual disease, MRD), in bone marrow (BM) samples.
2. If residual disease is detected in samples, characterise the single cell (sc) clonal architecture, epigenome and transcriptome and determine the leukemic stem cell content of the residual AML.
3. Perform an unbiased sc transcriptomic analysis of innate and acquired immune cells in BM, and peripheral blood (PB).
4. Test functional differences in comparable immune cells.

UK Mentor: Prof. Siim Pauklin
University:  Oxford, NDORMS
NIH Mentor: Dr. Udo Rudloff (NCI/CCR)
Project listed date: November 2020
Project: Identifying Regulators of Cancer Stem Cells in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies in human due to its late detection, highly metastatic characteristics, and poor responsiveness to current therapeutics. Pancreatic tumorigenesis involves a dedifferentiation process of cellular identity and the acquisition of a stem cell-like state of a subpopulation of cells known as cancer stem cells (CSCs). These cells are exceptionally important due to their higher therapeutic resistance and phenotypic plasticity that allows CSCs to metastasize and give rise to tumours. Currently, it remains largely unclear, which molecular markers and protein machineries control the stem cell-like identity of pancreatic CSCs. This knowledge would be valuable for earlier cancer detection and for developing more efficient pancreatic cancer therapeutics in the future.
The research objective of the project is to identify and characterize novel transcriptional regulators which govern gene expression of pancreatic cancer cells, particularly stem cell-like characteristics CSCs. The project will apply a broad range of cutting-edge research techniques such as 2D and 3D human cell culture systems, co-cultures of different cell types, next-generation single cell sequencing (scRNA-seq, scATAC-seq) of tumoural subpopulations in genetically engineered murine models (GEMMs) of pancreas cancer, functional studies (CRISPR/Cas9-mediated gene editing, tumour sphere assays), mechanistic studies (confocal microscopy, flow cytometry, cell sorting, CyTOF, western blotting), patient samples and mouse in vivo studies.
Collectively, this project will provide key insights to the signalling pathways and molecular mechanisms essential for the formation and maintenance of pancreatic CSCs, helping to better understand the tumorigenic process, and to uncover novel ways for diagnosing and treating this lethal cancer.

UK Mentor: Dr. Manuel Spitschan
University:  Oxford, Department of Experimental Psychology
NIH Mentor: Dr. Samer Hattar & Dr. Kathleen Merikangas (NIMH)
Project listed date: November 2020
Project: Mechanisms underlying the effects of light on physiology, behaviour and mental health in humans

Light exposure profoundly affects human physiology and behaviour. Light at the wrong time can shift the internal circadian rhythm and suppress the production of the endogenous hormone melatonin. These non-visual effects of light are largely mediated by the recently discovered melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), which are sensitive to short-wavelength (blue) light.

Chronic exposure to light at night can also have long-term consequences for health and well-being. Importantly, however, recent evidence shows that daytime light exposure can improve alertness and also offset the detrimental effects of light at night. Understanding what 'good' light exposure constitutes therefore is a key priority for mitigating circadian disruption by light.

This innovative collaborative research project will combine state-of-the-art laboratory and field assessments of circadian phase, melatonin production, visual and non-visual sensitivity, activity cycles, and other physiological and behavioural measurements. Broad training in a wide variety of techniques spanning circadian and visual neuroscience will be provided.

Recent publications:

Spitschan, M., Lazar, R., Yetik, E., & Cajochen, C. (2019). No evidence for an S cone contribution to acute neuroendocrine and alerting responses to light. Curr Biol, 29(24), R1297-R1298. doi:10.1016/j.cub.2019.11.031
Paksarian, D., Rudolph, K. E., Stapp, E. K., Dunster, G. P., He, J., Mennitt, D., . . . Merikangas, K. R. (2020). Association of outdoor Artificial Light at Night with mental disorders and sleep patterns among US adolescents. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2020.1935
Fernandez, D. C., Komal, R., Langel, J., Ma, J., Duy, P. Q., Penzo, M. A., . . . Hattar, S. (2020). Retinal innervation tunes circuits that drive nonphotic entrainment to food. Nature, 581(7807), 194-198. doi:10.1038/s41586-020-2204-1

UK Mentor: Prof. Nick Lakin & Prof Catherine Pears
University:  Oxford, Biochemistry
NIH Mentor:
Project listed date: November 2020
Project: Maintenance of genome stability through histone ADP-ribosylation

Maintaining genome integrity through DNA repair is critical for human health and defects in these pathways result in cancer, neurodegeneration and premature ageing. Understanding DNA repair mechanisms will provide insights into the underlying causes of these conditions and strategies for their treatment. For example, inhibitors of Poly(ADP-ribose) polymerases (PARPs), enzymes that regulate DNA strand break repair, are used to treat DNA repair deficient tumours, with the potential to treat other malignancies.

However, despite the use of PARP inhibitors in the clinic, the substrates modified by these enzymes and how they regulate DNA repair are ill-defined. For example, although histones are targets for ADP-ribosylation (ADPr) following DNA damage, how this regulates genome stability either directly, or through competition with other histone post-translational modifications (PTMs) is unclear.  This, in part, is due to the absence of an experimental platform in which PARPs and histone ADPr sites can be manipulated in tandem. These criteria are met in the eukaryotic model organism Dictyostelium and we have identified histone ADPr sites modified in response to DNA damage in this organism. We will exploit the unique ability to introduce site-specific ADPr mutations into endogenous Dictyostelium histone genes to define how ADPr regulates DNA repair either directly, or through influencing other histone PTMs. We will identify novel proteins that specifically interact with ADPr histones and characterise these factors in human cells. Together, this work will uncover how cells maintain genome integrity that will inform novel strategies to refine the use of PARP inhibitors in the clinic.

UK Mentor: Prof. Stephen Tucker
University:  Oxford, Physics
NIH Mentor:
Project listed date: November 2020
Project: Ion Channel Gating and Biophysics.  Non-canonical Methods of Ion channel Gating

We have been studying the mechanism of gating in the Two-Pore Domain (K2P) family of K+ channels and the way in which their gating can be regulated by lipids and small molecules.  It is now clear these channels use a variety of structural mechanisms to open and close their pores, including changes within the selectivity filter itself.  This mechanism of filter gating is also known to occur in other members of this superfamily of tetrameric cation channels including the BK Calcium-activated K+ channel and Cyclic Nucleotide Gated (CNG) channels.  In the proposed project the student would have the opportunity to combine multiple different biophysical, computational, and functional approaches to investigate the structural mechanisms of filter gating in these channels and investigate what properties might be common amongst these channels.

Rödström et al (2020) Nature 582:443-447. Schewe et al (2019) Science 363:875-880
Clausen et al (2017) PNAS 114:E8343-E8351 Schewe et al (2016) Cell 164:937-49.
Dong et al (2015) Science 347: 256-1259 Piechotta et al (2011) EMBO Journal  30: 3607-19

https://biophysics.physics.ox.ac.uk/tucker/index.html

UK Mentor: Prof. Manu Vatish
University:  Oxford, Nuffield Department of Women’s & Reproductive Health
NIH Mentor:
Project listed date: November 2020
Project: Preeclampsia is a multi-system hypertensive disorder of pregnancy that is caused by placental dysfunction.  The placenta releases extracellular vesicles (EVs) into the maternal circulation from early pregnancy all the way to term as part of its normal function. These EVs have proteins on the surface and contain genetic cargo, capable of altering maternal cellular function. It is known that the release, protein and genetic content of EVs is altered in preeclampsia. We have optimised an ex-vivo placental perfusion technique that permits isolation of trophoblast EVs. We have isolated EVs from normal and preeclampsia subjected these to proteomic and sequencing analysis. It is apparent that there are significant differences in miRNA and other non-coding RNA between EVs from normal and PE placentae. These differences have been validated by RT-PCR. We now wish to investigate the downstream cellular effects of the miRNAs/non-coding sequences, in cell models (endothelial, hepatic etc.) using transfected HEK293 cells. KEK293 cells constitutively produce exosomes. The transfected HEK293 cell will produce exosomes enriched for the RNA species of interest and allow specific miRNA effects to be determined using deep sequencing and proteomics analyses of the target cell. Analysis will require the candidate to be trained in bioinformatics approaches.
Simultaneously, we will interrogate a cohort of clinical samples for circulating miRNAs and investigate their role as a potential biomarker of placental function/disease. The NDWRH sits within the Women’s Centre at the John Radcliffe hospital and delivers 8000 women per year. 

UK Mentor: Prof. Sumana Sanyal
University:  Oxford, Sir William Dunn School of Pathology
NIH Mentor:
Project listed date: November 2020
Project: This project will investigate mechanisms of assembly, secretion and immune subversion adopted by (+)RNA viruses, with a particular emphasis on Dengue/Zika from the flavivirus and SARS-CoV-2 from the coronavirus families. Current understanding on how small (+)RNA viruses assemble and spread from cell to cell while evading innate and cellular immune responses is limited. Virus-infected cells induce selective autophagy of lipid droplets, which is accompanied by massive reorganisation of the host secretory pathway, but downregulate MHC-I and II restricted antigen presentation and often interferon production.

We have identified host factors that are targeted by viral proteins to induce autophagy-mediated LD hydrolysis (lipophagy) and unconventional secretory processes1,2. Collectively they are crucial for formation of viral replication compartments, assembly and cell-to-cell spread of virus progenies. We will apply CRISPR/Cas9 gene editing technology combined with biochemical and cell biological methods and functional assays to investigate how specific genes affect virus assembly and secretion. 

Infection by Dengue/Zika and SARS-CoV-2 also results in dramatic reduction of MHC-I and II restricted antigen presentation in monocytes and monocyte-derived cells. We will address how these viruses subvert innate and cellular immune responses to drive pathogenesis3,4. We aim to delineate biosynthesis, assembly, transport and turnover of MHC-molecules to define the specific steps targeted by these viruses. We will test E3 ligase candidates that are induced and copurify with MHC-I and II from virus infected cells, that may degrade or mis-sort MHC molecules to evade host immunity. We will combine quantitative mass spectrometry with complementary approaches in biochemistry, cell biology, immunology and virology to investigate the interplay of host cellular pathways such as autophagy, with that of virus biogenesis, and their mode of host immune evasion.

References:
1. Zhang, J. et al. Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy and Drive Virus Production. Cell Host Microbe 23, 819-831.e5 (2018).
2. Li, M. Y. et al. Lyn kinase regulates egress of flaviviruses in autophagosome-derived vesicles. Nature Communications 11:5189 (2020).
3. Jahan, A. S. et al. OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1. Cell Rep. 30, 1570-1584.e6 (2020).
4. Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection.(2020) doi:10.21203/rs.3.rs-63942/v1

UK Mentor: Dr. Andrew Blackford
University:  Oxford, Department of Oncology
NIH Mentor: Dr. Andre Nussenweig (NCI/CCR)
Project listed date: November 2020
Project: DNA mismatch repair is a system cells use to recognize and repair mis-incorporated DNA bases that can arise during DNA replication and recombination. Loss of mismatch repair activity causes a form of DNA hypermutability called microsatellite instability, and predisposes to colorectal, endometrial and other cancers. Recently, it was found that inhibition of the RecQ DNA helicase WRN specifically kills cancer cells with microsatellite instability1, thus providing an attractive drug target to treat cancers with defects in DNA mismatch repair. Unfortunately, small molecule inhibitors targeting WRN do not yet exist, but inhibitors that target the closed related RecQ DNA helicase BLM have already been developed. However, is still unclear whether and how BLM interacts with the DNA mismatch repair pathway.

The aim of this project will be to examine the physical, functional and genetic relationship between BLM and the mammalian DNA mismatch repair system in human cells as well as in mouse models. The student will have the opportunity to gain experience in super-resolution microscopy, CRISPR-Cas9 gene-editing, next-generation sequencing methods (including END-seq and GLOE-seq), mouse models and high-throughput screening for drug discovery, in addition to standard molecular and cell biology techniques.

1. van Wietmarschen et al., Nature 586, 292-298.

UK Mentor: Dr. David Dupret
University:  Oxford, MRC Brain Network Dynamics Unit at the University of Oxford, Nuffield Department of Clinical Neurosciences
NIH Mentor: Dr. Michael Krashes (NIDDK)
Project listed date: November 2020
Project: Humans and animals adjust their feeding behaviour according to many environmental factors, including the spatial context where food is found and consumed. Such contextual control of food seeking and eating is notably central to the ability to meet future needs and maximise chances of survival to changes in feeding routines, and may also impact abnormal feeding behaviour. However, the underpinning brain network mechanisms and pathways remain unclear. The Dupret laboratory (MRC Brain Network Dynamics Unit at the University of Oxford) investigates how the concerted spiking activity of neurons supports memory and the Krashes laboratory (NIH/NIDDK) investigates homeostatic and non-homeostatic feeding behaviour. An integrated project between the two labs, in collaboration with an NIH OxCam Scholar would be designed to enable the pursuit of a Ph.D. revealing circuit mechanisms of contextual control of feeding behaviour using in vivo large-scale network recordings in behaving rodents, combined with optogenetic and closed-loop manipulations.

UK Mentor: Prof Ellie Tzima
University:  Oxford, Radcliffe Dept. Of Medicine, Wellcome Centre
NIH Mentor:
Project listed date: November 2020
Project: Forces are important in the cardiovascular system, acting as regulators of vascular physiology and pathology. Vascular endothelial cells are constantly exposed to mechanical forces, such as shear stress, due to the flowing blood. Patterns of blood flow depend on blood vessel geometry and type and can range from uniform blood flow (which is protective) to disturbed blood flow (which is pathologic). Although we know that endothelial cells can sense and respond differently to different types of flow, the mechanisms by which they sense and respond to blood flow remain a mystery. Our laboratory has pioneered the studies of endothelial mechanosensing and has championed the use of a multi-disciplinary approach to this scientific problem. The focus of the proposed studentship is to identify mechanisms by which endothelial cells sense and respond to blood flow.  The student will have the opportunity to be exposed to a wide range of techniques based on the student’s individual interests that include: i) use of imaging and genetic approaches to characterize how mechanosensing affects disease intitiation and progression ; (2) applying high throughput RNA sequencing and proteomics approaches to globally dissect steps involved in disease aetiology; 3) use of bioinformatics and biochemical experimental approaches to understand the role of blood flow forces in cardiovascular disease.

Mehta V, Pang K, Rozbesky D, Nather K, Keen A, Lachowski D, Kong Y, Karia D, Ameismeier M, Huang J, Fang Y, Hernandez A, Reader JS, Jones EY, Tzima E. The Guidance Receptor Plexin D1 moonlights as an endothelial mechanosensor.2020 Nature Feb 5
https://pubmed.ncbi.nlm.nih.gov/32025034/

UK Mentor: Prof. Ira Milosevic
University:  Oxford, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine
NIH Mentor: Dr. Ling-Gang Wu (NINDS)
Project listed date: October 2020
Project: Amisyn at the crossing of modulated neurotransmission and brain pathologies

The human brain is astonishing: it is the source of our thoughts, actions, memories, perceptions and emotions. It confers on us the abilities that make us human, while simultaneously making each of us unique. Through deepened knowledge and understanding of how human brain works, we will comprehend ourselves better and treat brain diseases more incisively. Over recent years, neuroscience has advanced to the level that we can envision spanning molecules, cells and neuronal circuits in action. In particular, there is an emerging view that subtle aspects of presynaptic dysfunction are implicated in an increasing number of brain disorders such as neurological and neurodegenerative diseases.
We are particularly interested in exocytosis, a process of vital importance for neuronal cells that is controlled by a set of both positive and negative regulators. While promotors of exocytosis are well studied, negative regulators are poorly understood. We discovered that a small SNARE protein amisyn (STXBP6) acts as a vertebrate-specific competitor of synaptobrevin-2, a key player in exocytosis. Amisyn contains an N-terminal pleckstrin homology domain that mediates its transient association with the plasma membrane by binding to phospholipid PI(4,5)P2. Both the pleckstrin homology and SNARE domains are needed to inhibit exocytosis. Of note, amisyn is poorly studied despite several studies have emphasized its importance for exocytosis and reported the occurrence of amisyn mutations in autism, diabetes and cancer.
This PhD project aims to study mechanisms of exocytosis with a focus on amisyn. The candidate will study how lack or impaired function of amisyn modulates exocytosis, synaptic transmission and behavior. We have generated a mouse model without amisyn to be employed for these studies. In addition, our collaborative team has expertise in a wide variety of interdisciplinary techniques to support and facilitate the proposed PhD project, such as biochemical, (electro)physiologal and life confocal microscopy techniques.

UK Mentor: Prof. Andrew Blackford
University: Oxford, Department of Oncology
NIH Mentor: Dr. Andre Nussenzweig (NCI)
Project listed date: October 2020
Project: DNA mismatch repair is a system cells use to recognize and repair mis-incorporated DNA bases that can arise during DNA replication and recombination. Loss of mismatch repair activity causes a form of DNA hypermutability called microsatellite instability, and predisposes to colorectal, endometrial and other cancers. Recently, it was found that inhibition of the RecQ DNA helicase WRN specifically kills cancer cells with microsatellite instability1, thus providing an attractive drug target to treat cancers with defects in DNA mismatch repair. Unfortunately, small molecule inhibitors targeting WRN do not yet exist, but inhibitors that target the closed related RecQ DNA helicase BLM have already been developed. However, is still unclear whether and how BLM interacts with the DNA mismatch repair pathway.

The aim of this project will be to examine the physical, functional and genetic relationship between BLM and the mammalian DNA mismatch repair system in human cells as well as in mouse models. The student will have the opportunity to gain experience in CRISPR-Cas9 gene-editing, next-generation sequencing methods (including END-seq and GLOE-seq), mouse models, super-resolution microscopy and high-throughput screening for drug discovery, in addition to standard molecular and cell biology techniques.

1van Wietmarschen et al., Nature 586, 292-298.

UK Mentor: Prof. Sarosh Irani
University: Oxford, Nuffield Department of Clinical Neurosciences
NIH Mentor:
Project listed date: October 2020
Project: There are few examples of tractable overlaps between the fields of neurodegeneration and neuroimmunology. Yet, an immunological basis for a subset of patients with neurodegeneration would identify a group whose condition may be modified with the use of available immunotherapies. Dr Nath’s group have identified oligoclonal immunoglobulin bands in the cerebrospinal fluid of ~10% of patients with amyotrophic lateral sclerosis (ALS, also termed motor neuron disease). Further, endogenous retroviruses are observed to be activated in about 50% of ALS brains at autopsy. These observations mandate a search for the targets of the cerebrospinal fluid IgGs, to include retroviruses.

To identify antigenic targets, the DPhil candidate will use a variety of immunoassays established in both Dr Irani’s and Nath’s labs. These include B cell immunoglobulin heavy-light chain cloning, single cell RNA sequencing, western blotting, phage display screens and cell based assays.

In addition, these techniques will be applied to the cerebrospinal fluid of patients with Alzheimer’s disease to take an agnostic mass spectrometry based approach to identify antigenic targets of B cells and cerebrospinal fluid IgG in this cohort.

Overall, there will be excellent exposure to neuroimmunology and neuroinfection focused laboratories with the opportunity to learn multiple clinically applicable techniques to link common forms of neurodegeneration with a neuroinflammatory component.

UK Mentor: Prof. Nick Lakin
University: Oxford, Department Of Biochemistry
NIH Mentor:
Project listed date: October 2020
Project: Inhibitors of DNA repair have emerged as powerful agents in cancer therapy, either as monotherapies that exploit synthetic lethal interactions between DNA repair pathways, or by increasing the efficacy of chemo- and radiotherapies. Principal in this strategy is inhibition of Poly(ADP-ribose)-polymerases (PARPs), enzymes that regulate DNA strand break repair, and PARP inhibitors (PARPi) are being used to treat tumours with defects in homologous recombination (HR). However, this strategy is restricted to treating ovarian cancers, with limited information on why PARPi are toxic to HR-defective cells, or additional synthetic lethal interactions that will broaden their application to treat other tumours.

By combining our expertise in PARP biology and DNA repair (e.g. Ronson, et al. Nat Commun 9: 746) with cutting edge genome editing, proteomics and cell biology, this project will address this fundamentally important question by characterising novel cancer-related genes that are synthetic lethal with PARP dysfunction. Through a genome-wide CRISPR-Cas9 screen, we identified a novel gene (PASL9) that is synthetic lethal with PARPi. Our data indicate PASL9 is critical to resolve replication-associated DNA damage through a mechanism that is mutated in colorectal cancers. Through multidisciplinary hypothesis-driven research, this research will: a) Define the nature of synthetic lethality between PARPs and PASL9; b) Establish the repair mechanism regulated by PASL9; c) Assess PASL9 as a target to treat colorectal cancer. These studies will define the mechanistic basis of how PARPs and PASL9 maintain genome stability and define novel strategies to exploit PARPi to treat a variety of tumours.

UK Mentor: Prof. Sanjay Manohar
University: Oxford, Nuffield Department of Clinical Neuroscience
NIH Mentor:
Project listed date: October 2020
Project: Patients with neurological diseases often have difficulty in evaluating, planning and initiating actions. This can lead to disorders of motivation, such as apathy and impulsivity. My group studies the cognitive neuroscience of goal-directed action, in the context of disease. Some patients have difficulty  evaluating a particular plan in a given context. For example, they might revert to habitual actions which were previously associated with reward, or may be unable to think beyond their current situation. We take a multimodal approach, with behavioural studies, eye tracking, drug studies in healthy people and patients, EEG and neuroimaging. I have also developed computational models – both in the form of abstract cognitive models, and neural network simulations, to understand what the brain computes when determining actions.

My group has found that dopamine plays an important role in energising goal-appropriate actions. We hypothesise that prefrontal goal representations act through corticostriatal loops, being amplified or attenuated by dopamine.  In this project, the student will study patients with Parkinson’s disease and the effects of dopaminergic drugs on cognition, together with neuroimaging (which can include MEG or fMRI), to understand goal-directed action selection and energisation. The student will design their own behavioural tasks to separate out the component processes involved in maintaining and using goal information to energise actions. The student will test patients on their task, test drug mechanisms using a within-subject neuroimaging design, and  deploy appropriate analysis methods with help from a postdoctoral researcher.   The project will also include the opportunity to learn computational modelling if the student is keen.

UK Mentor: Prof. Anita Milicic
University: Oxford, The Jenner Institute
NIH Mentor:
Project listed date: October 2020
Project: Development of vaccines against existing complex diseases (such as malaria), or emerging pathogens, requires innovative approaches and the use of immune stimulants known as adjuvants. During an immune response to a vaccine, orchestrated cellular activation and leukocyte migration promote rapid changes throughout the body, from the site of injection to secondary lymphoid organs, such as the tissue draining lymph nodes and the spleen, to peripheral blood and the liver.
This project will focus on the characterisation of the adjuvant- and vaccine- induced innate and adaptive immune activation across these sites, with the analysis of the vaccine localisation (using intravital imaging and/or multiparameter flow cytometry) and the resulting cellular phenotypes within the innate and adaptive compartments. 
Studies will be based on a mouse model of malaria, using the malaria vaccine developed at the Jenner Institute, R21 - a virus-like particle (VLP) analogous to the currently most advanced malaria vaccine, GSK’s RTS,S in AS01 adjuvant. The R21 vaccine will be combined with new clinically relevant liposome- and emulsion-based adjuvants. The profiles of the immune response to different formulations will be correlated with protection against malaria.

Training will be provided in animal work procedures: immunisation, tissue sampling, producing and isolating Plasmodium parasites for malaria challenge, as well as a variety of immuno-profiling techniques, such as ELISA, ELISpot, multiparameter flowcytometry, bead-based cytokine arrays, CyTOF, confocal and intravital microscopy and other relevant approaches.

UK Mentor: Prof. Pedro Carvalho
University: Oxford, Sir William Dunn School of Pathology
NIH Mentor:
Project listed date: October 2020
Project: Mechanisms controlling organelle dynamics and quality control
Our lab is interested in membrane-bound organelles- how they form and acquire their distinctive proteome essential to carry their specialized functions. In particular, we focus on how organelle function is maintained through quality control processes. Our lab has been particular interested in a quality control process termed ERAD, which targets misfolded membrane proteins in the endoplasmic reticulum (ER). While some of the components of this process have been identified, the mechanisms by which diverse range of misfolded proteins are selected, ubiquitinated, extracted from the ER membrane and targeted for degradation by the proteasome remain elusive. To gain insight on the mechanisms of protein quality control our lab is taking multidisciplinary approaches. We are using CRISPR-based genome-wide genetic screens to delineate the molecular pathways involved in the degradation of disease-relevant misfolded proteins. In parallel, we use biochemical, proteomics and structural approaches to dissect mechanistically the multiple steps of ERAD. These studies will reveal the molecular basis of quality control processes by which misfolded and aggregation-prone proteins are handled by the cell both under normal and pathological situations. We are also interested in inter-organelle communications- which and how molecules are exchanged between organelles, which signals regulate those exchanges, etc.  Although we do mostly basic research, we are interested how these processes are disrupted in human disease.

References:
van de Weijer M, Krshnan L, Liberatori S, Guerrero EN, Robson-Tull J, Hahn L, Lebbink RJ, Wiertz E, Fischer R, Ebner D, Carvalho P (2020). Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex. Mol Cell.

Natarajan N, Foresti O, Wendrich K, Stein A, Carvalho P. (2020) Quality Control of Protein Complex Assembly by a Transmembrane Recognition Factor. Mol Cell.

Olzmann JA, Carvalho P. (2018) Dynamics and functions of lipid droplets. Nat Rev Mol Cell Bio

UK Mentor: Prof. Matthew Higgins
University: Oxford, Department Of Biochemistry
NIH Mentor:
Project listed date: October 2020
Project: The Higgins laboratory are expert in the structural studies of host-parasite interactions in parasitic diseases such as malaria. They study how interactions at the heart of processes such as erythrocyte invasion are mediated. They explore how parasite surface proteins manipulate the human immune system. They examine antibodies produced in response to human vaccination and determine how these function, and they use this information to design improved vaccine components.

For more information: higginslab.web.ox.ac.uk

To discuss possible projects, contact: matthew.higgins@bioch.ox.ac.uk

UK Mentor: Dr. Azim Ansari; Prof. Ellie Barnes; Prof. Philip Goulder
University: Oxford, Nuffield Department of Population Health
NIH Mentor:
Project listed date: October 2020
Project: Analyses of paired host-virus genomic data to understand disease heterogeneity of viral infections.

Genome-wide association studies (GWAS) aim to identify the genetic basis of phenotypic traits using the variation that exists within natural populations. Uniquely for infectious diseases, the inter-individual heterogeneity in disease phenotype is linked to both host and pathogen genetic variation. Traditionally, genetic studies of infectious diseases have sought to explain between-individual variation in disease phenotypes by assessing genetic factors separately in humans or pathogens, under the assumption that these factors are independent. Although reasonable for some variants, there is strong theoretical and empirical evidence that genetic interactions between host and viruses play a major role in viral disease aetiology.

In this project you will integrate host and viral genomic data from the same patients to better understand viral pathogenesis and between-individual heterogeneity in disease outcomes. By analysis of paired host-virus genomic data from well-characterised cohorts you will gain novel insights on (a) host polymorphisms linked with viral sequence variation, (b) virus sites under strong host genetic selective pressures, (c) host and virus genetic factors independently contributing to disease phenotypes and (d) host-virus genetic interactions contributing to disease phenotypes. The findings have the potential to: (I) revolutionize our understanding of host-virus interactions and human biology; (II) aid in development of more effective vaccines, drug targets and immunotherapies; and (III) permit better use of therapies through patient stratification. In the age of “Big Data” and “Personalised Medicine”, analysis of paired host-pathogen genomic data will become increasingly important to uncover the mechanisms driving pathogen adaptations and heterogeneity of infection outcomes.

UK Mentor: Dr. Azim Ansari; Prof. Ellie Barnes; Prof. Philip Goulder
University: Oxford, Nuffield Department of Population Health
NIH Mentor:
Project listed date: October 2020
Project: Understanding mechanisms of sex disparities in infectious diseases

The mortality rate for COVID-19 pandemic has been two-fold higher in men than women. Similar observation extends to susceptibility and outcome of most other infectious diseases. For instance, after initial Hepatitis C Virus infection women are 2-3 times more likely to spontaneously clear the virus without any interventions and in HIV infection females are 5 times more likely to achieve elite control (complete suppression virus without therapy) than men. However, a consequence of the more vigorous immune response observed in females is more immunopathology and auto-immune diseases (such as lupus) in women than men. For the same reasons, females make stronger immune responses to vaccines but suffer more adverse events. Despite large evidence for sex differences in autoimmune diseases and susceptibility and outcome of infectious diseases, data addressing the biological mechanism are remarkably scarce.

In this project you will use computational and experimental methods to probe differences in immune system that lead to sex differences in infectious diseases. We will investigate this question across many infections including HCV, HBV, HIV and COVID-19. You will start with analysing the available RNA-seq and genomic data from our cohorts and other public databases to understand the role of heterogeneity in X chromosome inactivation in female immune cells and the transcriptional consequence and its contribution to better outcome in infectious diseases. In the next stage you will stimulate male and female immune cells with different immunogens and perform single cell RNA-sequencing to evaluate differential responses across distinct cell types and their association with sex. The project will also use samples and data from vaccine clinical trials. The baseline samples will be compared to the post-vaccination samples and differences in immune systems between sexes will be investigated.

UK Mentor: Prof. Aiden Doherty
University: Oxford, Nuffield Department of Population Health
NIH Mentor: Dr. Charles Matthews (NCI)
Project listed date: September 2020
Project: What types of physical activity are associated with a lower incidence of cancer?

At the National Cancer Institute, we have demonstrated that higher levels of moderate to vigorous intensity physical activity are associated with a lower risk of cancer, including cancer in the breast, colon, endometrium, bladder, kidney, and stomach1. However, due to a reliance on self-reported measures of physical activity, a number of key questions remain unanswered on what overall volume of physical activity, and what types of physical activity, are associated with lower cancer risk. In addition, previous studies are observational by nature and are therefore unable to determine causality due to unmeasured or residual confounding.

At Oxford, our group has shown that wearable sensors such as wrist-worn accelerometers can be used to noninvasively measure physical activity status in large-scale biomedical studies. For example, we have measured physical activity status in 103,712 UK Biobank participants who agreed to wear a wrist-worn accelerometer for seven days2. These measurements are now actively used by health researchers worldwide to demonstrate that simple measures of overall activity are cross-sectionally associated with cancer outcomes3. However, no large study of device measured physical activity has yet taken place to assess associations with incident cancer outcomes with sufficient longitudinal follow-up. Furthermore, activity trackers often capture ~180 million data points/participant/week and therefore have the potential to identify other powerful behavioural signals to detect future cancer risk.

Machine learning methods can help maximise the utility of data from wearable sensors. These methods attempt to automatically detect patterns in data and then use those uncovered patterns to predict future data. Our group has demonstrated the utility of supervised machine learning to identify sleep and functional physical activity behaviours from raw accelerometer data4. However, there is a broad concern around the lack of reproducibility of machine learning models in health data science5. It is therefore important to carefully consider how to promote robust machine learning findings and reject irreproducible ones, to ensure credibility and trustworthiness.

This DPhil project therefore proposes to use the world’s largest available datasets to investigate what types of physical activity are associated with a lower incidence of cancer. Working with colleagues at the University of Oxford and the National Cancer Institute, you will have the opportunity to address the following important questions:

1. What behavioural measurements of physical activity status can be reliably ascertained from accelerometer datasets?
You will have the opportunity to develop reproducible machine learning skills to develop methods to identify physical activity behaviours from raw accelerometer datasets. Specifically, you will develop semi-supervised machine learning methods which seek to combine supervised methods (good quality labels, small datasets) with unsupervised methods (no labels but large datasets which are less prone to sampling bias). This will involve use of the largest available accelerometer datasets with reference measurements for physical activity behaviours in free-living environments (using wearable cameras)6.

2. What physical activity behaviours are associated with incident cancer events?
Here, you will have the opportunity to develop new skills in epidemiological data analysis. You will have the opportunity to use the UK Biobank dataset which has collected wrist worn accelerometer data from 103,712 participants2. This dataset includes information on participants’ first hospital admission or death from cancer, identified from linkages to the national death index, Hospital Episode Statistics, and cancer registries.

3. Are physical activity behaviours potentially causally associated with cancer?
You will have the opportunity to develop genetic epidemiology skills by implementing two-sample Mendelian Randomization7 to assess potential causal effects of accelerometer measured physical activity and cancer. For cancer outcomes, summary genetic association data will be obtained from existing collaborators from International cancer consortia.

Candidates should have a BSc, or ideally MSc, in a discipline with a substantive epidemiological, computational, or quantitative component. We very much welcome prospective candidates to directly contact us to further develop this proposal.

References
1. Matthews, C. E. et al. Amount and intensity of leisure-time physical activity and lower cancer risk. J. Clin. Oncol. 38, 686–698 (2020).
2. Doherty, A. et al. Large Scale Population Assessment of Physical Activity Using Wrist Worn Accelerometers: The UK Biobank Study. PLoS One 12, e0169649 (2017).
3. Barker, J. et al. Physical activity of UK adults with chronic disease: cross-sectional analysis of accelerometer-measured physical activity in 96 706 UK Biobank participants. Int. J. Epidemiol. (2019). doi:10.1093/ije/dyy294
4. Willetts, M., Hollowell, S., Aslett, L., Holmes, C. & Doherty, A. Statistical machine learning of sleep and physical activity phenotypes from sensor data in 96,220 UK Biobank participants. Sci. Rep. 8, 7961 (2018).
5. Beam, A. L., Manrai, A. K. & Ghassemi, M. Challenges to the Reproducibility of Machine Learning Models in Health Care. JAMA (2020). doi:10.1001/jama.2019.20866
6. Doherty, A. et al. GWAS identifies 14 loci for device-measured physical activity and sleep duration. Nat. Commun. 9, 5257 (2018).
7. Kazmi, N. et al. Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian-randomization study based on 79 148 prostate-cancer cases and 61 106 controls. Int. J. Epidemiol. (2019). doi:10.1093/ije/dyz235

UK Mentor: Prof. Laura Parkkinen
University: Oxford, Nuffield Department of Medicine
NIH Mentor: (TBD)
Project listed date: September 2020
Project: Development of multiplex RT-QuIC assay for the early detection of dementia and movement disorders: step towards personalized medicine

Alzheimer disease (AD), dementia with Lewy bodies (DLB) and Parkinson disease (PD) are the most common neurodegenerative diseases that create an enormous public health burden with a rapidly aging population. There is currently no definitive test that allows doctors to determine if someone has or will get one of these disorders. At present, the diagnosis is purely based on the symptoms, but by the time this is made the disease process is already too advanced for any therapies to have full impact. There is a clear and urgent need for reliable diagnostic tests that can identify early signs of dementia and movement disorders, and methods that can distinguish between the different types of neurodegeneration e.g. AD / DLB / PD so that drug treatment can be prescribed in a patient specific manner. Early, sensitive and reliable diagnostics will inevitably open an invaluable window for not only to early treatment but also towards finding a cure.

The intention of this DPhil project is to develop such a diagnostic method where samples taken from patients can be  interrogated using a highly sensitive and specific clinic-ready technique/ “kit” called Real-Time Quaking-Induced Conversion (RT-QuIC). An RT-QuIC method, which detects multiple sticky proteins in cerebrospinal fluid (CSF) as a surrogate marker of brain pathology has already been established by the Parkkinen lab to identify signs of early onset Parkinson’s disease (http://www.bbc.co.uk/news/health-37196619). Our aim here is to develop complementary RT-QuIC methods for AD and DLB patients. We anticipate that this will serve as a powerful predictive tool for patients at high risk of developing dementia i.e. patients with mild cognitive impairment, and enable a personalised test that can identify specific variants of the disease. In addition, we are using the RT-QuIC method to understand the disease pathogenesis, particularly the role of different conformational variants, or “strains” of proteins that may contribute to the tremendous heterogeneity of neurodegenerative diseases by showing different morphology, seeding and/or cross-seeding propensities, strain-specific neuropathology and different levels of neurotoxicity.

The proposed project will require vast biochemical, biophysical, molecular neuroscience and pathological skills and knowledge provided by the unique translational training environment formed by Dr Parkkinen and her local and international collaborators who are all experts on the field. Dr Parkkinen’s Molecular Neuropathology research group is based at state-of-the-art facilities at the Academic Unit of Neuropathology (AUN) and Oxford Brain Bank which are part of the Nuffield Department of Clinical Neurosciences (NDCN) in the University of Oxford. Research into neurodegenerative diseases has a high priority and profile within the University of Oxford and especially NDCN. Dr Parkkinen is also an integral part of the Oxford Parkinson’s Disease Centre (www.opdc.ac.uk) which is a multidisciplinary group of internationally recognised scientists with strengths in genomics, imaging, neuropathology, biomarkers and cell and animal models. Regular meetings are arranged for all post-graduate students within AUN/NDCN, and feedback and guidance is provided to ensure completion of the degree within the allocated time. All the necessary funding is provided by Dr Parkkinen’s successful Weston Brain Institute and Parkinson’ UK grants. 

UK Mentor: Prof. Goylette Chami
University: Oxford, Nuffield Department of Population Health
NIH Mentor: Dr P’ng Loke (NIAID)
Project listed date: August 2020
Project: Immuno-parasitology and clinical epidemiology of schistosomiasis

There is a pressing need to improve the understanding of morbidity for schistosomiasis. These parasitic blood flukes afflict over 250 million people worldwide. For Schistosoma mansoni (a species that causes the intestinal form of schistosomiasis), untreated individuals can develop severe or functional morbidities such as enlarged livers/spleens, periportal fibrosis, oesophageal varices, anaemia, and chronic gut inflammation. The onset and progression of these morbidities is a complex interplay of host immunology, environmental factors, coinfections, and social determinants. This project is an exciting opportunity to combine work in immunology with epidemiology. The candidate will gain skills in both wet lab work and fieldwork in Uganda. You will join multidisciplinary labs at the NIH and Oxford. The overall goal of this project will be to establish immunological profiles for schistosomiasis-associated morbidities. Immunological profiles (based on flow cytometry and cytokine production) of infected individuals may help identify relationships between clinical outcomes and the immunological mechanisms behind fibrosis, hepatosplenomegaly and other clinical signs of severe or chronic disease. Inter-human variation will be explored.

UK Mentor: Prof. Richard Maude
University: Oxford, Nuffield Department of Medicine
NIH Mentor: Dr. Stefan Jaeger (NLM)
Project listed date: August 2020
Project: Smartphone based image analysis for malaria diagnosis

The goal of this project is to develop the system for real-world use for malaria diagnosis. It will include optimisation of the system at NIH and testing of the system in the field at MORU. This will comprise several stages: 1. Testing and optimisation of the smartphone application interface and performance at NIH; 2. Testing and optimisation of the system for connecting the smartphone to standard light microscopes at NIH and at MORU in Bangkok; 3. Development of a core set of performance metrics for the application; 4. Preliminary field testing of the entire system for malaria diagnosis together with government healthcare workers and National Malaria Control Programme staff in Bangladesh and Thailand; 5. Structured interviews to gather feedback on the system and its potential role in malaria diagnosis in different settings; 6. Formal field trial of the system; 7. Development of a system implementation guidance document for National Malaria Control Programmes.

UK Mentor: Prof. Ana Domingos
University: Oxford, Department of Physiology, Anatomy & Genetics
NIH Mentor: (TBD)
Project listed date: August 2020
Project: The Domingos laboratory researches neuroimmune mechanisms underlying obesity. We discovered the sympathetic neuro-adipose junction, a functional synapse-like connection between the sympathetic nervous system and white adipocytes (Cell 2015). We found that this neuro-adipose junction is necessary and sufficient for fat mass reduction via norepinephrine (NE) signaling (Cell 2015, Nature Comm 2017). We then discovered Sympathetic neuron-Associated Macrophages (SAMs) that directly import and metabolize NE. Abrogation of SAM function promotes long-term amelioration of obesity independently of food intake (Nature Medicine, 2017). Given the recent discovery of SAMs, virtually nothing is insofar known about the cell biology of these cells or what other immune cells populate the SNS to cross talk with SAMs. This PhD project aims to uncover  biological mechanisms of SAM biology. Using single cell sequencing methods, the student will unravel the heterogeneity of the sympathetic neuro-immune cross talk involving SAMs. By identifying novel immune cell mediators, we will have a better understanding of how SAMs are regulated, and pave the way to the identification of cellular and molecular targets that would then be amenable to drug delivery. We will be guided by singe cell sequencing dataset for formulating hypothesis that model fundamental aspects regarding the biology of these cells. The interactions between SNS axons and SAMs, or other resident cells identified by single cell sequencing, will be resolved by super resolution microscopy and 3D reconstruction, for a better understanding of the intricate topology of SAMs’ morphology in relation to SNS axons (Nature Medicine 2017). The PhD candidate can also use optogenetics to probe neuro-immune interactions (as in Nature Medicine 2017), as well as 3DISCO imaging for mapping the distribution of the aforementioned cells in adipose tissues. This project will give a candidate a tremendous opportunity to apply cutting-edge methods in the growing field of neuroimmune biology.
References:
Zeng W*,  Pirzgalska RM*;  et al  Domingos AI (2015). Sympathetic Neuro-Adipose Connections Mediate Leptin-Driven Lipolysis. Cell.
Features:
—Ruud&Bruening (2015). Metabolism: Light on leptin link to lipolysis. Nature
—Bray( 2015). Zapping fat in WAT, NatureRev.Neuroscience
—News & Views (2015).  A closer look at the nerves that slim down your fat cells, Science
—Varela & Horvath (2015). A Sympathetic View on Fat by Leptin, Cell
2. Pereira MMA,  et al, Domingos, AI A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages. (2017) , Nature Communications.
3. Roksana M Pirzgalska*, et al, Christopher K Glass & Ana I Domingos (2017). Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nature Medicine. 
Features:
—Jung, S (2017). Year in Review. Nature Reviews Immunology
—Bradley, C (2017). Specialized macrophages contribute to obesity. NatureRev.Endocrinol.
—Scanlon, S (2017). Unusual macrophages contribute to obesity. Editor's Choice, Science
—Czech, MP (2017). Macrophages dispose of catecholamines in adipose tissue. NatureMedicine
—Guttenplan et al. (2018). Play It Again, SAM: Macrophages Control Peripheral Fat Metabolism, TrendsImmunology

UK Mentor: Dr. Timothy SC Hinks
University: Oxford, Nuffield Department of Medicine
NIH Mentor: Dr. Stewart J Levine, Laboratory of Asthma and Lung Inflammation, NHLBI
Project listed date: August 2020
Project: To investigate how apolipoproteins modify immune cell function in innate and adaptive airway inflammatory cells

Asthma is the world’s commonest chronic lung disease, affecting 350 million people worldwide. The advent of novel ‘biologic’ therapies targeting specific phenotypes of asthma is currently revolutionizing the treatment of patients with type 2 inflammation. However, there are no specific treatments available for the 50% of patients with type 2 low disease. The Levine group has identified a novel pathobiologic mechanism involving dysregulation of apoplipoproteins, which may play an important role in this phenotype by regulating the recruitment and function of innate and adaptive immune cells, which may have relevance for resistance to corticosteroids. Peptide mimetics of these molecules have potential as novel therapies for asthma, especially for patients with type 2 low neutrophilic inflammation. Dr Hinks group uses in vitro, murine and ex vivo human studies on highly phenotyped asthmatics to explore the biology of the inflamed airway mucosa, particularly innate and adaptive immune cells. Through this collaboration the student would use a range of techniques and a mix of wet lab science and human experimental medicine to understand the translational potential of apolipoprotein biology in human asthma.

UK Mentor: Prof. Ervin Fodor
University: Oxford, Dunn School of Pathology
NIH Mentor: Dr. Jonathan Yewdell (NIAID)
Project listed date: September 2019
Project: Study cell and molecular biology of influenza A virus replication

UK Mentor: Prof. Christophe Fraser
University: Oxford, Big Data Institute
NIH Mentor: Dr. Thomas Quinn (NIAID)
Project listed date: September 2019
Project: Understanding HIV incidence at a population level is critical for monitoring the epidemic and understanding the impact of interventions. Using full length sequencing of HIV we are developing models for estimating incidence based on viral diversity which increases with time in the infected host. Using data from longitudinal cohorts we will develop these models and then apply them to large population based interventions to determine their impact.  Experimental approaches include next-generation sequencing, phylogenetic analysis, modelling and statistical methodologies.

UK Mentor: Prof. Christophe Fraser & Prof. Katrina Lythgoe
University: Oxford, Big Data Institute
NIH Mentor: Dr. Thomas Quinn (NIAID)
Project listed date: September 2019
Project: In this project you will use state-of-the-art viral sequencing data, combined with epidemiological data and mathematical modeling, to create an integrated understanding of HIV transmission. HIV places an enormous burden on global health. Implementing treatment and interventions can save millions of lives, but to do this effectively requires us to be able to predict the outcome of interventions, and to be able to accurately assess how well they are working once implemented. For HIV, these efforts are hampered by long durations of infections, and rapid within-host viral evolution during infection, meaning the virus an individual is infected with is unlikely to be the same as any viruses they go on to transmit.
 
For this project, you will identify individuals enrolled in the Rakai Community Cohort Project, based in Uganda, who are part of possible transmission chains, and for whom multiple blood samples are available throughout infection and at the time of transmission. These samples will be sequenced using state-of-the-art technology developed at the University of Oxford enabling the sequencing of thousands of whole virus genomes per sample, without the need to break the viral genomes into short fragments (whole-haplotype deep sequencing). Using this data, you will comprehensively characterize viral diversity during infection and at the point of transmission. Key questions you will tackle are:
 
- Do ‘founder-like’ viruses (similar to those that initiated infection) persist during chronic infection?
- Is there a consistent pattern of evolution towards population consensus virus?
- Are ‘founder-like’ viruses, or ‘consensus-like’ viruses more likely to be transmitted?
- Does the transmission of drug-resistant virus depend on the history of the transmitting partner?

UK Mentor: Prof. John Frater (Oxford)
University: Oxford, Nuffield Department of Medicine
NIH Mentor: Multiple potential NIH collaborators
Project listed date: September 2019
Project: 1. Biomarkers of the HIV reservoir and remission in primary HIV infection
2. Simultaneous host and pathogen 'omics to interrogate the HIV reservoir
3. Microfluidic and Lab-on-a-Chip approaches to characterising the HIV reservoir

UK Mentor: Prof. John Frater 
University: Oxford, Nuffield Department of Medicine
NIH Mentor: 

Project listed date: September 2019
Project: Biomarkers and Immunogenicity of the HIV reservoir in primary HIV infection

This project will explore ex vivo the characteristics of those cells which may contribute to persistent HIV infection. Undertaken in state-of-the-art facilities at the Peter Medawar Building in the University of Oxford, the project will combine flow cytometry, cell sorting and gene expression approaches (including RNAseq and single cell technologies) to characterise in detail those cells that contain latent HIV infection. Applying these techniques to individuals who stop antiretroviral therapy and are monitored longitudinally for viral rebound will allow further definition of the environment in which viral transcription is initiated.

The candidate will map the immune responses of individuals started on early antiretroviral therapy to determine how these are impacted by starting ART and which components of the immune response correlate with the reservoir and persisting viraemia. Additionally, samples from individuals under-going treatment interruption will allow further detailed  characterisation of immune correlation of rebound and remission.

The candidate will combine flow cytometry and molecular techniques to help clarify the phenotype of cells latently infected with HIV. Further objectives will explore changes in cell phenotype and gene expression profile that associate with rebound viraemia. Additionally, exploration of the antigen-specificity of latently infected cells through other approaches such as TCR sequencing and the ability to which these cells can be targeted by the immune system will be a parallel component of this project.

UK Mentor: Prof. John Frater 
University: Oxford, Nuffield Department of Medicine
NIH Mentor: 
Project listed date: September 2019
Project: Simultaneous host and pathogen ’omics to interrogate the HIV reservoir

The aim of this project will be to apply Next Generation Sequencing (NGS) approaches simultaneously to both host and the HIV provirus. The candidate will apply and improve methods to produce full-length viral haplotype and integration site data (already developed in the lab) from cohorts of individuals with treated early HIV infection, many of whom will receive experimental interventions and stop antiretroviral therapy.

Simultaneously, unbiased transcriptomic profiling (RNASeq) and analysis of DNA accessibility (ATAC-Seq) will be incorporated to allow a global interrogation of viral and host genomics, with potential to extend this to single cell analyses. Following method development, clinical samples from UK cohorts will be analysed to characterise the reservoir and to inform the source of rebound viraemia on treatment interruption. The work will therefore have both a cross-sectional and longitudinal component, promising significant analytical power. Working collaboratively with other group members and projects to link cell phenotype and subset with viral phylogenetics to identify the source of viraemia will be an important part of the work.

The candidate would be expected to have interests in both the laboratory wet-lab and bioinformatic components of the project, to achieve a unified problem-solving approach.

UK Mentor: Prof. Stephen Goodwin (Oxford) & Prof. Steve Russell (Cambridge)
University: Oxford, Department of Physiology, Anatomy and Genetics & Cambridge, Department of Genetics 
NIH Mentor: Dr. Brian Oliver (NIDDK)
Project listed date: September 2019
Project: Genomic and genetic basis of sex differences in development, physiology, and behavior

UK Mentor: Prof. Véronique Gouverneur 
University: Oxford, Department of Chemistry
NIH Mentor: Dr. Victor Pike (NIMH)

Project listed date: September 2019
Project: Invent and implement new radioactive probes for imaging specific molecular targets in animal and human brain with positron emission tomography

UK Mentor: Prof. Philipp Kukura
University: Oxford, Department of Chemistry
NIH Mentor: Dr. Antonina Roll-Mecak (NINDS / NHLBI)
Project listed date: September 2019
Project: The tubulin code in health and disease

UK Mentor: Prof. Trudie Lang
University: Oxford, Nuffield Department of Medicine
NIH Mentor: 
Project listed date: September 2019
Project: Clinical Trial Methodology In Developing Countries

UK Mentor: Prof. Xin Liu (Oxford)
University: Oxford, Nuffield Department of Medicine
NIH Mentor: Multiple potential NIH collaborators
Project listed date: September 2019
Project: Crosstalk between the tumour suppressor p53 and inflammation pathways

UK Mentor: Prof. Jane McKeating
University: Oxford, Nuffield Department of Medicine
NIH Mentor: Prof. Jake Liang (NIDDK)
Project listed date: September 2019
Project: Regulation of Hepatitis B Virus Infection by Hypoxic Signalling Pathways

Viruses are obligate parasites that have evolved to manipulate their host to their advantage. Chronic viral infection of the liver is a global health problem, with over 270 million individuals infected with hepatitis B (HBV) virus that causes liver disease which can progress to liver cancer. HBV is the number 8 killer worldwide and is associated with 800,000 deaths/year with limited therapies, highlighting an urgent need for new curative treatments.

We recently discovered that low oxygen environments, naturally found in the liver, enhance HBV replication at several steps in the viral life cycle. Cellular response to low oxygen is regulated by a family of oxygenases and hypoxia inducible factors (HIFs) that control genes involved in energy metabolism and other cellular processes. This project will study the role of hypoxic signalling and other related pathways in HBV replication and their impact on immune based and epigenetic therapies.

The successful candidate will investigate the molecular mechanisms underlying these observations. In particular, we will (i) identify the role of HIFs in HBV cccDNA biogenesis, transcription and metabolism, and production of infectious particles; (ii) analyse how these host-virus interactions are shaped by the tissue microenvironment, genetic manipulations and metabolic parameters. The project has basic and translational research components and applies state-of-the-art technologies, tools and model systems to study HBV infection and its mechanism of disease. Taken together, this exciting project builds on strong preliminary results and existing expertise that may lead to new therapeutic targets and antiviral development.

UK Mentor: Prof. Chris O'Callaghan
University: Oxford, Nuffield Department of Medicine
NIH Mentor: Dr. Chris Hourigan (NHLBI)
Project listed date: September 2019
Project: It is well recognized that acquired genetic mutations are an important cause of cancer, but recent studies have suggested that such somatic mutations are also associated with atherosclerosis. Somatic mutations have been found in blood from 10% of people over 70 years of age and 20% of people over 90 years of age and appear associated with an increased risk of atherosclerotic disease. Although age is a known independent risk factor for atherosclerosis, the basis for this has not been known.  It now appears likely that these mutations, several of which are found in genes known to regulate inflammation and immunity, are either a direct contributor to, or a potential biomarker for, this age-associated risk. The challenge now is to identify molecular mechanisms linking these somatic mutations with atherosclerosis.

This PhD project will investigate the cellular and molecular basis of the association between age associated DNA mutations and atherosclerotic disease risk. To do this will require cross-disciplinary collaboration, so this project brings together two highly complementary groups to address this important new biomedical challenge. At the National Heart, Lung and Blood Institute of the NIH, Chris Hourigan works on these acquired mutations in the context of a blood cancer called acute myeloid leukemia. At Oxford, Chris O’Callaghan works on molecular mechanisms involved in atherosclerosis and the genetic control of those mechanisms, especially in vessel wall inflammation.

This is a very exciting new field and has potential to identify new drug targets and so benefit patients with atherosclerosis. The experience gained by this doctorate will be highly relevant to other fields and will include cellular and molecular biology, high throughput sequencing approaches including single cell approaches and analysis of genetic variation.

UK Mentor: Prof. Jens Rittscher 
University: Oxford, Nuffield Department of Medicine
NIH Mentor: Dr. David Wink (NCI/CCR)
Project listed date: September 2019
Project: Conprehensive quantitative assessment of tissue biopsies in 3D

UK Mentor: Prof. Kevin Talbot & Prof. Dame Kay Davies
University: Oxford, Nuffield Department of Medicine & Department of Physiology, Anatomy and Genetics
NIH Mentor: Dr. Kenneth Fischbeck (NINDS)

Project listed date: September 2019
Project: Understand the disease mechanism and potential treatments of the polyglutamine expansion diseases that include Huntington's disease and muscular dystrophy

UK Mentor: Prof. Holm UhligDr. Arian Laurence
University: Oxford, Nuffield Department of Medicine
NIH Mentor: Dr. Behdad (Ben) Afzali (NIDDK)
Project listed date: September 2019
Project: Investigating the role of transcription factor networks in T cell immunoregulatory fate decisions

Regulatory T cells expressing the FoxP3 transcription factor (Tregs) are arguably the most important naturally-occurring anti-inflammatory cells in the body and are prime candidates for cellular therapy of autoimmunity and transplant rejection. They are potently immunosuppressive, indispensable for maintaining self-tolerance and in resolving inflammation. Tregs can be induced to develop dichotomously from naïve precursors that also have the ability to differentiate into inflammatory T cell lineages. The choice of differentiation pathway (“fate decisions”) is directed by environmental signals and interplay between many transcription factors working within networks. The expression of many genes is required for a healthy immune response and this is highlighted by the discovery of many gene mutations that are associated with very early onset auto-immune disease.

Our goal is to understand how transcriptional signals from the environment are integrated in T cells to determine inflammatory versus regulatory T cell differentiation and the quality and duration of effector function. Experimental approaches will involve genomics of patients with primary immuno-deficiencies and very early onset colitis, next generation sequencing platforms (RNA-seq, ChIP-seq, Cut&Run, ATAC-seq, scRNAseq), molecular and cell biology, CRISPR genome editing and in vivo murine models.

UK Mentor: Prof. Peijun Zhang
University: Oxford, Nuffield Department of Clinical Medicine
NIH Mentor: Dr. Avindra Nath (NINDS)
Project listed date: September 2019
Project: Determining the role of endogenous retroviruses in the pathophysiology of neurological diseases

Retroviral sequences remain dormant in the human genome and occupy nearly 7-8% of the genomic sequence. We have shown that one of these viruses termed HERV-K (HML-2) is activated in patients with amyotrophic lateral sclerosis (ALS), and transgenic animals that express the envelope protein of HERV-K develop ALS like symptoms. Hence, we are now using a wide variety of structural biology and virology tools to determine the mechanism by which its expression is regulated and causes neurotoxicity to motor neurons. 

UK Mentor: Prof. Peijun Zhang
University: Oxford, Nuffield Department of Clinical Medicine
NIH Mentor: 
Project listed date: September 2019
Project: Structural mechanisms of HIV-1 inhibition by host cell factors using cryoEM

Infections by retroviruses, such as HIV-1, critically depend on the viral capsid. Many host cell defence proteins, including restriction factors Trim5α, TrimCyp and MxB, target the viral capsid at the early stages of infection and potently inhibit virus replication. These restriction factors appear to function through a remarkable capsid pattern sensing ability that specifically recognizes the assembled capsid, but not the individual capsid protein. Using cutting-edage cryoEM technologies, we aim to determine the molecular interactions between the viral capsid and host restriction factors that underpin their capsid pattern-sensing capability and ability to inhibit HIV-1 replication. Specifically, we will combine cryoEM and cryoET with all-atom molecular dynamics simulations to obtain high-resolution structures, together with mutational and functional analysis, as well as correlative light and cryoEM imaging of viral infection process, to reveal the essential mechanism for HIV-1 capsid recognition and inhibition of HIV-1 infection. Information derived from our studies will allow to design more robust therapeutic agents to block HIV-1 replication.

UK Mentor: Prof. Peijun Zhang
University: Oxford, Nuffield Department of Clinical Medicine
NIH Mentor: 
Project listed date: September 2019
Project: Structure and dynamics of bacterial chemotaxis signalling array by cryoEM.

Bacterial chemotaxis response is crucial for colonization and infection, and the signal transduction systems that mediate such responses are potential new targets for antimicrobial drug development. Such system has emerged as a paradigm for understanding the principles of intracellular signal transduction both in bacterial and eukaryotic cells. In bacterial cells, hundreds of basic core signalling units consisting of three essential components, the chemoreceptors, the histidine kinase and the adaptor protein, assemble into a two-dimensional lattice array which allows cells to amplify and integrate many varied and possibly conflicting signals to locate optimal growing conditions. We aim to determine the structure and dynamics of the chemotaxis signalling arrays using state-of-the-art cryo-electron microscopy and tomography. We will take both in vitro and in situ structural approaches and combined with large-scale all atom molecular dynamic simulations. The ultimate goal is to assemble a time-resolved molecular movie of the entire signalling pathway in bacterial chemotaxis at an atomic level. 

UK Mentor:  Prof. Lidia Vasilieva
University: Oxford, Department of Biochemistry
NIH Mentor: Dr. Eugene Valkov
Project listed date: September 2019
Project: Molecular mechanisms of mRNA degradation

The regulation of gene expression by controlling the production and stability of messenger RNA (mRNA) in the context of the cellular environment is critical for normal cell function. Imbalance in mRNA levels is deleterious for the cell as well as the organism. The exosome is a key mediator of 3′-to-5′ exo- and endonucleolytic RNA degradation and has a central role in maintaining proper mRNA levels in the nucleus and the cytoplasm in eukaryotes (Kilchert et al., 2016 Nature RMCB). However, the exosome is rather unspecific and has a low intrinsic nucleolytic activity and, currently, we do not understand how the exosome targets specific mRNAs for efficient degradation. This has important clinical implications as dysregulation of the exosome function leads to severe neurological diseases such as spinal muscular atrophy, pontocerebellar hypoplasia, and infantile leukodystrophy. Learning more about the mechanisms that underpin exosome regulation will, in turn, help us to understand how these pathogenic states arise in humans in instances where exosome function is perturbed. Highly conserved proteins that interact with the 5′-terminal methylguanylate cap structure on mRNAs such as Cbc20, Cbc80, and Ars2 have been implicated in the regulation of RNA degradation and gene silencing mediated by the exosome complex.

In this project, we aim to understand the function of Cbc20, Cbc80 and Ars2 by studying in molecular detail how these factors guide the targeting and activation of the exosome. The project will bring together two highly complementary host laboratories (headed by Dr. Lidia Vasilieva at the University of Oxford and Dr. Eugene Valkov at the NCI/NIH in Frederick, U.S.A.) to address this important biological problem. Both laboratories will synergize to apply the latest biochemical, structural, genetic and transcriptomic approaches to ensure an excellent training opportunity in multidisciplinary molecular biology. In the course of their doctoral studies, the student will receive extensive training in protein production and purification, X-ray crystallography and/or single-particle cryoEM, functional biochemistry, genetics and functional genomics. Production and reconstitution of multisubunit complexes, as well as functional biochemical and transcriptomic analyses, will be carried at Oxford whilst the structural aspects of the project will be at the NIH. New mechanistic insights into the function of the exosome cofactors will be highly impactful and advance our understanding of how they regulate the exosome function in controlling the stability of individual mRNA targets. This fundamental new knowledge will advance our understanding of how cells execute different programs of gene expression in health and disease.

UK Mentor: Prof. Fumiko Esashi
University: Oxford, Dunn School of Pathology
NIH Mentor: Dr. Vladimir Larionov (NCI)
Project listed date: October 2019
Project: The aim of this project is to exploit the human artificial chromosomes (HAC) to understand human disease associated with chromosome instability and to develop new strategy for therapeutic treatments.

UK Mentor: Prof. Pedro Carvalho
University: Oxford, Dunn School of Pathology
NIH Mentor:
Project listed date: October 2019
Project: My lab is interested in understanding how membrane-bound organelles form and acquire their distinctive proteome essential to carry their specialized functions. In particular, we focus on how organelle function is maintained through quality control processes, such as protein degradation. We are also interested in inter-organelle communications- which and how molecules are exchanged between organelles, which signals regulate those exchanges, etc.  Although my lab does mostly basic research, we are interested how these processes are disrupted in human disease.

UK Mentor: Prof. Philip Biggin
University: Oxford, Biochemistry
NIH Mentor: No
Project listed date: October 2019
Project: Computational investigation of ligand-binding with a particular emphasis on membrane proteins. (See sbcb.bioch.ox.ac.uk/bigginlab for an overview of the lab).

UK Mentor: Prof. Katja Simon
University: Oxford, NDORMS
NIH Mentor: No
Project listed date: October 2019
Project: Are metabolites generated by the microbiota key to a young immune system?

UK Mentor: Dr. Natalia Gromak
University: Oxford, Dunn School of Pathology
NIH Mentor: Dr. Robert J. Crouch, (NICHD)
Project listed date: October 2019
Project: Unusual RNA/DNA structures (R-loops) are formed when the RNA hybridizes to a complementary DNA strand, displacing the other DNA strand in this process. R-loops are formed in all living organisms and play crucial roles in regulating gene expression, DNA and histone modifications, generation of antibody diversity, DNA replication and genome stability. R-loops are also implicated in human diseases, including neurodegeneration, cancer mitochondrial diseases and HIV-AIDs.

Collaboration between Prof Crouch (NIH) and Dr. Gromak (Oxford) labs will focus on understanding the regulation of R-loops and uncover the molecular mechanisms which lead to R-loop-associated diseases. We will employ state-of-the-art techniques including CRISPR, Mass Spectrometry and molecular biology approaches to understand the principles of R-loop biology in health and disease conditions. In the long term the findings from this project will be essential for the development of new therapeutic approaches for R-loop-associated disorders.

UK Mentor: Prof. Armin Lak
University: Oxford, Physiology, Anatomy & Genetics
NIH Mentor: Dr. Andrew Holmes (NIAAA)
Project listed date: October 2019
Project: Probing the roles of medial frontal cortical neurons and neuromodulators in decision making


Andrew Holmes’ Lab (NIH/NIAAA) and Armin Lak’s Lab, Oxford University
Several decades of research has shown that medial frontal cortical neurons, as well as the neuromodulatory system that innervate the medial frontal cortex, notably the dopamine system, are important in reward valuation and decision making. However, it is not known whether different regions of medial frontal cortex play distinct roles in guiding decisions. Moreover, the role of frontal dopamine signals in shaping and regulating decisions has yet to be established. To address these questions, this project will use a combination of large-scale Neuropixels recording across the medial frontal cortex, as well as optical measurement of dopamine release in the medial frontal cortex during decision making in mice. At Oxford, the project will use Neuropixels probes to record the activity of many neurons across different regions of medial frontal cortex while mice perform a task that systematically manipulates the value of choice options. This data will allow us to investigate the relation between frontal neuronal activity and decision-making variables, and characterize distinct roles of different medial frontal regions in choice behavior. At NIH, the project will take advantage of optical and genetic methods to measure the dynamics of dopamine release in frontal cortical regions identified in the electrophysiological recordings. These experiments will reveal the roles that frontal dopamine play during decision making. In analyzing the electrophysiological and optical data, we will use computational models of learning and decision making to relate neuronal signals with trial-by-trial model-driven estimates of decision variables. The project is primarily experimental in nature but will provide an opportunity to develop computational skills. Together, the project will provide fundamental insights into behaviorally-relevant computations that neurons across the medial frontal cortex perform during decision making, and will reveal the roles of frontal dopamine signals in shaping choice behavior. For more information please visit: https://www.niaaa.nih.gov/laboratory-behavioral-and-genomic-neuroscience and https://www.laklab.org.

Cambridge

UK Mentor: Dr. Stefano Pluchino
University: Cambridge, Clinical Neurosciences
NIH Mentor: Dr. Isabel Beerman (NIA)
Project listed date: November 2020
Project: Stem cells of the ageing MS brain
Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system, which currently lacks restorative therapies. Transplantation of neural stem cells (NSCs) has been shown to promote healing of the injured CNS, but previous work has demonstrated that NSCs from patients with PPMS are prematurely senescent. Cellular senescence causes a pro-inflammatory cellular phenotype that impairs tissue regeneration. Senescence in PPMS NSCs was found to be associated with increased secretion of HMGB1, a pro-inflammatory alarmin found to inhibit oligodendrocyte differentiation, and also found increased within white matter lesions of PPMS autopsy tissue. This project aims to understand the role of HMGB1 in PPMS NSC senescence using techniques such as CRISPR-Cas9, RNA sequencing, and functional NSC assays. The longterm goal of this project will be to determine the cause of senescence in NSCs from patients with PPMS and if these cells are suitable for therapeutic use.

UK Mentor: Prof. Ross Waller
University: Cambridge, Biochemistry
NIH Mentor: Dr. Michael Grigg (NIAID)
Project listed date: October 2020
Project: Apicomplexan pathogens are highly-adapted intracellular parasites of humans causing disease including malaria, toxoplasmosis and cryptosporidiosis. These parasites actively confront, subvert and defend themselves against host immune attack using a complex suite of parasite surface and secreted proteins that hijack immune signalling pathways. Moreover, transmission and generation of genetic novelty occurs in definitive hosts where differentiation into sexual parasite forms occurs. Relatively little is known, however, of the molecules and processes that drive these events, particularly during the sexual stages of parasite development. This project will use new methods in in vitro culture of sexual development in Toxoplasma, advanced methods for global spatial characterisation of parasite cell proteomes in order to identify specific proteins thought to be implicated in these interactions, and then utilise CRISPR/cas9 mutagenesis tools to engineer pools of strains deficient in these specific proteins. By assaying mutant pools both in vitro, and through the definitive host we will identify proteins and processes required for sexual stage conversion.

UK Mentor: Dr. Amanda Sferruzzi-Perri
University: Cambridge, Physiology, Development and Neuroscience
NIH Mentor:
Project listed date: October 2020
Project: Obesity during pregnancy affects maternal and infant health both during pregnancy and for long afterwards. It raises the risk of health complications like maternal diabetes during pregnancy, and increases the susceptibility of the mother to develop metabolic syndrome in the years after delivery. It also leads to neonatal and later life health complications in their infants, such that infants are more prone to develop metabolic impairments themselves in later life. Despite this, the mechanisms operating during pregnancy that lead to these poor pregnancy outcomes in obese women, remain unknown. The placenta is the organ that produces hormones responsible for changing the metabolism of the mother to ensure sufficient nutrients are available for fetal growth during pregnancy. However, to date, little is known about the role of placental hormone production in the development of maternal metabolic complications in pregnancies where the mother is obese. This study aims to identify the importance of placental hormone production for maternal metabolism and fetal growth in pregnancies where the mother is obese. It will use samples from pregnant mice that are lean or obese (due to a diet high in sugar and fat) and omic approaches (RNAseq/mass spec) on fluorescence-activated sorted placental endocrine cells to identify the hormones disrupted by maternal obesity with metabolic effects. It will also use metabolic, molecular, mitochondrial and biochemical assays to assess the mother’s ability to use glucose and respond to insulin in obese mice with and without a genetic defect in the placenta that disrupts placental hormone production. Finally, hormones identified to be importance in maternal metabolic regulation in mouse pregnancies will be quantified in the plasma of lean and obese women to determine if they relate to pregnancy outcome.

UK Mentor: Prof. David Ron
University: Cambridge, Cambridge Institute for Medical Research
NIH Mentor: Dr. Alan Hinnebusch (NICHD)
Project listed date: October 2020
Project: Molecular Mechanism of the Integrated Stress Response
A signalling pathway linking nutrient availability to changes in gene expression that hinges on the phosphorylation of translation initiation 2 (eIF2) has long been known to exist. Recognized initially as the yeast General Control Response, recent convergent lines of research have implicated its metazoan counterpart, the Integrated Stress Response, in diverse physiological processes ranging from immunity to memory formation.

This PhD programme will exploit our emerging detailed understanding of translation initiation and termination to shed light on unanticipated mechanistic aspects of the ISR. An understanding of these details may inform efforts to target the ISR to therapeutic ends.

UK Mentor: Dr. Julian Rayner
University: Cambridge, CIMR
NIH Mentor: Dr. Steve Holland (NIAID)
Project listed date: October 2020
Project: There are more than 200 million clinical cases of malaria each year, leading to nearly half a million deaths, primarily among children in Africa. The two major tools for malaria control, antimalarial drugs and insecticides, are both seriously threatened by resistance, making the search for a highly effective malaria vaccine more urgent than ever. My lab focuses on the malaria parasite blood stages, during which parasites invade, multiply inside and consume human erythrocytes. The process of erythrocyte invasion represents a brief extracellular window in the parasite life cycle when parasites are exposed to the antibody-mediated immune system, making it a potential vaccine target. A number of vaccine-related projects are available that intersect with the interests of NIH collaborators in the NIAID Malaria Research Program, from systematic screening of new potential vaccine candidates, to deep structural understanding of current high-profile candidates, to understanding natural immunity to malaria in order to inform better vaccine design. All could involve a mix of new technologies, cutting edge experimental genetics, parasite biology and the opportunity to contribute to the long-term battle against one of humanities oldest and most persistent infectious disease foes.

UK Mentor: Prof. Lalita Ramakrishan
University: Cambridge, Department of Medicine
NIH Mentor: Dr. Steve Holland (NIAID)
Project listed date: October 2020
Project: TB remains the biggest infectious killer in the world despite >50 years of antimicrobial therapy. 10 million people get TB each year of whom nearly 2 million succumb to it. Yet this burden represents only 5-10% of those who get infected; 90% clear the infection on their own. Both the Ramakrishnan and the Holland labs are trying to solve the puzzle of why some individuals get TB disease. The two labs take different and complementary approaches to the problem. Holland runs an internationally known referral service that takes care of a unique cohort of patients with genetic susceptibility to nontuberculous mycobacterial infections. In the lab, they have mapped these susceptibilities to varied immune genes – IRF8 and GATA-2, myeloid growth factors, IL-12R, the GTPase Rac2, to name only a few. How and whether deficiencies in these genes causes susceptibility to TB remains a black box. Ramakrishnan’s approaches afford the opportunity to open this black box.

Her group has pioneered the optically transparent and genetically tractable zebrafish infected with Mycobacterium marinum as a model for TB. The use of the zebrafish has enabled discoveries about TB immunopathogenesis and the genetic basis of susceptibility to TB which has led to the discovery of a variety of inexpensive, approved drugs that can be used to treat TB, often in a patient genotype-directed manner.

Through this joint project, the two labs will work together to harness the power of the zebrafish to understand the molecular and cellular basis of the human susceptibilities identified by Holland. The student will move between humans and fish (and Bethesda and Cambridge) to uncover fundamental mechanisms of mycobacterial disease pathogenesis while acquiring mastery over the disciplines immunology, infectious diseases, genetics, molecular biology and cell biology.

UK Mentor: Dr. Yorgo Modis
University: Cambridge, Department of Medicine
NIH Mentor: Dr. Joseph Marcotrigiano (NIAID)
Project listed date: October 2020
Project: All viruses deliver or generate RNA in the cytosol. Long cytosolic dsRNAs are recognized by the innate immune sensor MDA5. My group has shown that MDA5 assembles into filaments on dsRNA, which activates the signaling hub protein MAVS and induces a potent antiviral interferon response.

UK Mentor: Dr. Catherine J. Merrick
University: Cambridge, Pathology
NIH Mentor:
Project listed date: October 2020
Project: My group studies the human malaria parasite Plasmodium falciparum.  Collaborative PhD projects can be offered in research areas centred around Plasmodium DNA biology: we are particularly interested in the molecular mechanisms underlying DNA replication and cell cycle control in Plasmodium, which replicates by an unusual method called schizogony.  We are also interested in mechanisms for silencing and promoting the recombination of a family of key virulence genes called var genes - particularly the role that G-quadruplex DNA structures may play in var gene control.  In fact, we have recently discovered that G-quadruplexes and their helicases have more general roles in genome stability and evolution in the malaria parasite as well.

UK Mentor: Prof. Edmund Kunji
University: Cambridge, MRC Mitochondrial Biology Unit
NIH Mentor: Dr. Lucy Forrest (NIAID)
Project listed date: October 2020
Project: The mitochondrial pyruvate carrier (MPC) is critical for cellular homeostasis, as it transports pyruvate, the end product of glycolysis, from the cytosol into the mitochondrial matrix, where it enters the Krebs cycle. Dysfunction of MPC has been implicated in many diseases and MPC is being investigated as a drug target for the treatment of cancer, non-alcoholic fatty liver disease, Parkinson’s disease and diabetes, because of its central role in metabolism. MPC is a heterodimeric complex of two small homologous membrane proteins, called MPC1 and MPC2 (1, 2). There is currently no structure and the molecular transport mechanism has not been elucidated. The aim of this project is to characterise the MPC complex with respect to its structure and mechanism, and to develop it further as a drug target.

The Forrest lab (NIH-NINDS) uses bioinformatics, structural modelling, and molecular simulations to study integral membrane proteins. The lab focuses on transporters, and in particular, those that harbour mechanistically-relevant symmetries, and has successfully predicted important functional properties of many different transport proteins (3-5). The lab also develops novel bioinformatic tools, such as the sequence alignment software, AlignMe, aimed at improving structural modelling approaches for membrane proteins (6).

The Kunji lab (University of Cambridge) has developed methods to purify the MPC complex, to reconstitute it into liposomes, and to study its transport properties (1, 2). In addition, it has developed methods to study the binding of small molecules to the MPC complex, opening the way to find specific inhibitors, which could be developed further as drug leads. The lab also uses advanced x-ray crystallography and cryo-EM techniques to obtain the structures of highly dynamic mitochondrial transporters, for example the mitochondrial ADP/ATP carrier (7).

UK Mentor: Prof. Zoe Kourtzi
University: Cambridge, Psychology
NIH Mentor: Dr. Peter Bandettini (NIMH)
Project listed date: October 2020
Project: Ultra-high field imaging of adaptive brain circuits
The human’s brain capacity for sensory plasticity has been studied mainly in the context of neurodevelopment (i.e. critical periods) and pathology (e.g. amblyopia) with interventional approaches (e.g. sensory deprivation) that result in drastic brain re-organisation. Yet, understanding the brain plasticity mechanisms that mediate subtler changes in perceptual judgments through shorter-term experience and training remains a challenge. 
This project focuses on the brains ability to improve perceptual skills at the core of visual recognition through training; that is, the ability to detect the features of an object from cluttered backgrounds and discriminate whether they belong to the same or different objects. Learning and experience have been suggested to facilitate this ability to translate complex patterns of visual information into perceptual decisions. We will exploit methodological advances in high-field (7T) brain imaging to investigate functional and neurochemical brain plasticity mechanisms at finer-scale. We will test the hypothesis that perceptual learning is implemented by feedback and inhibitory mechanisms that re-weight sensory information across stages of processing (from early to higher visual cortex). In particular, the high resolution of 7T imaging allows us to measure functional signals in different cortical layers. We will test whether learning alters fMRI activation patters in deep—rather than middle—layers in the visual cortex, consistent with feedback processing. Further, advances in MR Spectroscopy enable us to test the role of GABA—the primary inhibitory neurotransmitter for brain plasticity—in perceptual learning. We will test whether learning-dependent changes in GABA relate to changes in functional brain activity and improved behavioural performance in perceptual tasks. Investigating these core mechanisms of brain plasticity will advance our understanding of how the brain optimises its capacity to support adaptive behaviour through learning and experience.

UK Mentor: Dr. Helle Jorgensen
University: Cambridge, Department of Medicine
NIH Mentor: Prof. Carsten Bonnemann
Project listed date: October 2020
Project: Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of cardiovascular diseases such as atherosclerosis, which cause heart attack and stroke. In healthy vessels, VSMC contraction regulate blood flow and blood pressure. In response to injury and inflammation, however, the cells lose their contractile function and undergo extensive transformation. This process results in the generation of a wide spectrum of phenotypically changed cells within atherosclerotic lesions, which are predicted to impact differently on disease progression. Using clonal lineage tracing in mouse models of atherosclerosis, we demonstrated that disease-associated cell accumulation result from extensive proliferation of a small subset of VSMC that can generate the full range of distinct cells. By combining lineage tracing with single cell RNA sequencing (sc-RNAseq) in mouse models, we have identified signatures of VSMC-derived cells subpopulations. Interestingly, cells displaying mesenchymal stem cell character are rare in healthy vessels and their numbers increase in disease models. The aim of this project is to study the function of specific VSMC-derived cell populations in human disease using a combination of genomics and functional assays. This work is important for efficient cell targeting in atherosclerotic lesions.

UK Mentor: Dr. Rita Horvath
University: Cambridge, Clinical Neurosciences
NIH Mentor: Prof. Carsten Bonnemann (NINDS)
Project listed date: October 2020
Project: Developing novel treatments for children with inherited neurological diseases
Inherited neurological disorders are disabling, progressive, often fatal conditions, representing an enormous unmet medical need with devastating impacts on affected families, the healthcare system, and the economy. There are no cures and the limited therapies available treat symptoms without addressing the underlying disease.

Next-generation sequencing has facilitated a molecular diagnosis for many inherited neurological disorders, such as mitochondrial diseases and other neuromuscular diseases, which are the focus of this research. The development of targeted therapies requires detailed laboratory investigation of molecular and mutational mechanisms, and a systematic evaluation of well-chosen agents as well as gene and transcript directed strategies using standardized experimental systems. Our research is focusing on understanding the molecular pathogenesis of childhood onset inherited neurological diseases, such as mitochondrial disease and other neuromuscular diseases to develop targeted therapies.

Using a translational approach, we aim to
1. understand the clinical course of patients in relation to the underlying disease mechanism
2. delineate the mutational and molecular mechanisms of the molecular defect in the appropriate cell types by developing model systems such as induced neuronal progenitor cells (in vitro) and zebrafish (in vivo)
3. improve the treatment options for patients by developing novel therapies that are directed at these mechanisms, including directly at the genetic mutation or resulting transcript.

We use a combination of exome sequencing, genome sequencing, and other omics technologies to identify novel disease genes and disease mechanisms. By functional evaluation in vitro (induced neuronal progenitor cells) and in vivo (zebrafish) we confirm pathogenicity and uncover molecular mechanisms of disease. To address the mutational mechanisms, we use gene transfer, splice modulation, allele silencing and CRISPR/cas systems.

UK Mentor: Dr. Ingo Greger
University: Cambridge, MRC-LMB
NIH Mentor: Dr. Wei Lu (NINDS)
Project listed date: October 2020
Project: Molecular studies of excitatory and inhibitory CA1 synapses in synaptic plasticity
A balance between neuronal excitation and inhibition is crucial for normal brain physiology; upsetting this balance underlies various brain pathologies. To shed light on the molecular underpinnings of this regulation at the synapse level, this project will investigate the dynamics of glutamate- and GABA-A synapses and receptors in CA1 hippocampus under baseline conditions and in response to synapse potentiation. Specifically, using structural, functional and imaging approaches we will study both, spiny glutamatergic and aspiny GABA-ergic CA1 synapses and associated receptor complexes (AMPA-type glutamate and GABA-A) and how these change at the synapse- and receptor levels in response to LTP (long-term potentiation) induction. Our aim will be to monitor changes of glutamatergic and GABAergic synapses and receptors at pyramidal neurons (glutamate) and/or parvalbumin-positive (PV+) interneurons at various points after LTP induction. We will monitor changes in synapse size and receptor composition using advanced imaging and electrophysiological approaches.

UK Mentor: Prof. Ed Bullmore; Prof. Petra Vertes
University: Cambridge, Department of Psychiatry
NIH Mentor: Dr. Armin Raznahan
Project listed date: October 2020
Project: The current project has a core emphasis on quantitative methods for analysis of complex brain networks and neuroimaging data. It will build on our prior work in one of 2 broad directions and will be tailored based on the incoming student’s scientific and training goals:

1.       Innovative methods for human brain network mapping, and large-scale applications to population and clinical neuroscience.
The last ten years have witnessed rapid growth in the application of network science to the understanding of human brain organization. Within this framework, the brain is described as a network whose nodes represent large-scale anatomical brain regions and whose links represent structural or functional connections derived from neuroimaging data. We have previously applied these non-invasive macroscopic methods to characterize both adult brain networks and their change during development and ageing, in health and in disease. We are now beginning to develop network-based biomarkers that can help stratify patient populations in clinically useful ways.
To progress this broad agenda, the current project could include for example:

·         Developing new methods to combine structural MRI with additional in vivo imaging modalities (e.g. resting-state functional MRI).
·         Applying novel network-based markers recently developed in our labs to an accelerated longitudinal neuroimaging dataset on adolescence, to uncover how different trajectories of adolescent brain change link to variation in behavior, psychiatric risk and other demographic and societal factors.

2.       Novel methods for cross-species or multi-scale data integration.
Developing principled prognostics and interventions will also depend upon our understanding of how microscopic biological mechanisms shape macroscopic brain networks in health and in disease. For example:
·         We recently proposed a "transcriptional vulnerability hypothesis" which posits that the spatial pattern of disease-related brain changes in various psychiatric disorders (measured by MRI) is predicted by expression patterns for disease-relevant genes across the healthy brain. Since many disorders can be best characterized by changes in brain network connectivity, it would be hugely beneficial to develop next-generation neuroinformatic tools that relate disease-specific changes in MRI connectivity (at the edge-level) to gradients in gene expression between pairs of brain regions. This project could form the basis for predictive models of selective brain vulnerability to neuropsychiatric disease.
·         Translational studies of human and animal MRI networks will be crucial to uncovering the biology of mental health disorders. There are a number of opportunities for extending MRI connectomic analyses from human to 9.4T animal imaging (in rodents and marmosets) in the context of development, addiction, anxiety and depressive disorders. Network-level changes in these animal models can then be further investigated with neural, pharmacological, histological and genomic methods.

UK Mentor: Prof. Clare Bryant
University: Cambridge, Department of Veterinary Medicine
NIH Mentor: Dr. Raphaela Goldbach-Mansky
Project listed date: October 2020
Project: The inflammasome consists of a cytosolic NOD-like receptor, an adaptor molecule (ASC) and an effector molecules caspase 1.  Once activated the inflammasome processes inflammatory cytokines such as interleukin 1 beta (IL1B) and IL18 as well as driving an aggressive form of cell death (pyroptosis).  Inflammasomme protein complexes are central to sustaining inflammation in acute diseases (like COVID-19 associated ARDS) or chronic conditions (such as Alzheimer’s Disease, Parkinson’s, diabetes, arthritis).  Patients with rare autoactivating mutations in the NLR proteins have basally active inflammasomes leading to severe autoinflammatory syndromes. How inflammasome complexes form within the cell, particularly in patients with autoactivating mutations in NLRs are poorly understood.   The aims of this project are as follows:
1.      Identify the molecular mechanisms by which the gain of function mutations causes constitutive activation of the NLRs
2.      Determine why gain of function mutations in different NLRs (NLRP3 and NLRC4) result in differences in inflammasome cytokine production with NLRP3 biased towards IL1B and NLRC4 towards IL18
3.      Visualise how gain of function mutations alter inflammasome formation by visualising the protein complexes at super resolution and atomic resolution


This project will study how the inflammasome forms using state of the art microscopy techniques including live super resolution imaging and cyroelectron microscopy tomography.  The consequences of the gain of function mutations on inflammasome formation will be studied using these techniques in cell lines where the key proteins are tagged and the gain of function mutations introduced by CRISPR/Cas9 (many of which are already available within the laboratory).  This work will be extended to consider cells from patients with these diseases to map back the biology and the imaging onto the cell line models.   

Mentor: Prof. Esther B. E. Becker
University: Oxford, DPAG
NIH Mentor:
Project listed date: January 2020
Project: Functional analysis of disease genes causing cerebellar disorders
Our group is interested in the genetic, molecular and cellular mechanisms that underlie disorders of the cerebellum such as cerebellar ataxia but also autism and language disorders.  Ongoing work in our group is aimed to elucidate the underlying pathogenic mechanisms of novel genetic disorders affecting the cerebellum. Our approach is multi-disciplinary and employs a variety of methods including the generation and characterization of novel mouse models, functional experiments in cell lines and primary neurons, as well as modelling of identified patient mutations and their effects using human induced pluripotent stem cells combined with genome engineering.

UK Mentor: Prof. Franklin Aigbirhio
University: Cambridge, Department of Neuroscience
NIH Mentor: Dr. Victor Pike (NIMH)
Project listed date: September 2019
Project: Invent and implement new radioactive probes for imaging specific molecular targets in animal and human brain with positron emission tomography

UK Mentor: Dr. Tristan Barrett
University: Cambridge, Department of Radiology
NIH Mentor: Multiple NIH collaborators
Project listed date: September 2019
Project: Radiology - Prostate Cancer Imaging

UK Mentor: Prof. Andreas Bender
University: Cambridge, Department of Chemistry
NIH Mentor: Dr. Richard Eastman & Dr. Rajarshi Guha (NCATS)
Project listed date: September 2019
Project: Predicting the Efficacy of Drug Combination Therapy in Cancer and Malaria

UK Mentor: Prof. Andreas Bender
University: Cambridge, Department of Chemistry
NIH Mentor: Dr. Scott Auerbach, Dr. Nicole Kleinstreuer, & Dr. Nisha Sipes (NIEHS)
Project listed date: September 2019
Project: Combined Computational-Experimental Approaches to Predict Acute Systemic Toxicity

UK Mentor: Prof. Guy Brown
University: Cambridge, Department of Biochemistry
NIH Mentor: Unspecified
Project listed date: September 2019
Project: Roles of microglial phagocytosis in neurodegeneration

UK Mentor: Prof. Folma Buss
University: Cambridge, Department of Clinical Biochemistry
NIH Mentor: Dr. Sarah Heissler (NHLBI)
Project listed date: September 2019
Project: TBA

UK Mentor: Prof. Carlos Caldas
University: Cambridge, Department of Oncology
NIH Mentor: Dr. Louis Staudt (NCI)
Project listed date: September 2019
Project: 

UK Mentor: Dr. Patrick Chinnery
University: CambridgeDepartment of Clinical Neurosciences
NIH Mentor:
Project listed date: September 2019
Project: The role of mitochondrial DNA mutations in neurological diseases and ageing

Mitochondrial DNA (mtDNA) mutations have emerged a major cause of neurological disease and may also contribute to the ageing process – but their origin is not well understood. Remarkably, we have shown that most humans harbour a mixture of mutant and wild-type mtDNA (heteroplasmy) at very low levels. Our aims is to understand how mtDNA mutations arise, how they are inherited, and how they accumulate in specific tissues, particularly in the nervous system. Harnessing this knowledge, we will develop new treatments targeting the mitochondrion.

UK Mentor: Dr. Menna Clatworthy
University: Cambridge, Department of Medicine
NIH Mentor: Dr. Claudia Kemper (NHLBI)
Project listed date: September 2019
Project: Investigating the impact of dendritic cell-T cell interactions on autocrine complement activation in CD4 T cells

In this project, we will investigate how different stimuli including IgG-immune complexes and TLR ligands affect the ability of DCs to influence T cell autocrine complement regulation. This is of relevance to our understanding of how inflammation is propagated in autoimmunity and for vaccination boost strategies.

UK Mentor: Dr. Mark Evans
University: Cambridge, Department of Medicine
NIH Mentor: Dr. Michael Krashes (NIDDK)
Project listed date: September 2019
Project: This project aims to determine how changes in blood glucose can affect hunger and the drive to feed and examine how this can be altered in conditions such as diabetes.

Hypoglycaemia (low blood glucose) is a complication of the treatment of diabetes with insulin. It is feared by people with diabetes and is associated with increased risk of death. One of the important defences against a falling blood glucose is the generation of hunger- a potent defence which both warns and directs towards corrective action to help restore blood glucose. A subset of people with diabetes develop defective defensive responses to and warning symptoms (including hunger) of hypoglycaemia. This puts them at a markedly increased risk of suffering severe episodes of hypoglycaemia.

We want to determine how hypoglycaemic feeding is triggered and the mechanisms by which this may become altered in diabetes. To examine this in murine models, we will combine the skills of Evans’ laboratory (hypoglycaemia, insulin clamp methodology, operant conditioning feeding assessment) located within the Institute of Metabolic Science with broader interest and expertise in appetite and feeding with Krashes’ laboratory (neurocircuitry of feeding) to examine how and where glucoprivic feeding maps onto both conventional feeding pathways and also the neurocircuitry which triggers other counter-regulatory responses to hypoglycaemia. The student will examine how this adapts after exposure to antecedent hypoglycaemia. Finally, they will examine potential therapeutic targets to boost/ restore or prevent the loss of protective hunger in diabetes with recurrent hypoglycaemia.

UK Mentor: Prof. Andres Floto
University: CambridgeDepartment of Medicine
NIH Mentor: Dr. Steve Holland (NIAID) & Dr. Ken Olivier (NHLBI)
Project listed date: September 2019
Project: Nontuberculous mycobacteria (NTM) represent the most common mycobacterial infection in the developed world and are often difficult or impossible to treat. While exposure of humans to NTM is almost universal (most species are ubiquitous in the environment), pulmonary infection only occurs in certain individuals, suggesting a strong genetic contribution to host susceptibility.

Nontuberculous mycobacteria (NTM) represent the most common mycobacterial infection in the developed world and are often difficult or impossible to treat. While exposure of humans to NTM is almost universal (most species are ubiquitous in the environment), pulmonary infection only occurs in certain individuals, suggesting a strong genetic contribution to host susceptibility.
Our proposal aims to use both forward and reverse genetics to define and characterise host restriction factors for NTM infection.
 
The project will employ the following orthogonal experimental approaches:
1) We will functionally test the impact of genetic polymorphisms, identified through the NIH whole exome sequencing study of NTM-infected individuals and family pedigrees ( Ref) using CRISPR-Cas9 genomic editing of macrophages and IPSC-derived epithelial cells.
 
2) In parallel, we will undertake an unbiased forward genetic screen using an established and validated genome-wide CRISPR-Cas9 macrophage library to phenotypically screen for mutants with defective restriction of intracellular NTM.
 
Validated hits from both approaches will be prioritised, based on novelty and effect size, for further analysis to examine (a) their molecular mechanism of action (using advanced cell imaging and biochemical techniques), (b) their effect on in vivo infection (using established fly, fish, and mouse models); and (c) the impact of potential therapeutic manipulation of implicated pathways  as host-directed therapy.

UK Mentor: Prof. Rebecca Fitzgerald
University: CambridgeMRC Cancer Unit
NIH Mentor: Dr. Christian Abnet (NCI/DCEG)
Project listed date: September 2019
Project: Genetics of squamous cell carcinoma - identifying high risk groups

UK Mentor: Prof. Robin Franklin
University: Cambridge, Department of Clinical Neuroscience 
NIH Mentor: Dr. Daniel Reich (NINDS)
Project listed date: September 2019
Project: Examine the dynamics of oligodendrocyte lineage cells in murine and primate models of multiple sclerosis using a combination of imaging, histopathological, and molecular techniques

UK Mentor: Prof. Christoph Hess
University: Cambridge, Department of Medicine
NIH Mentor: Dr. Michael Lenardo (NIAID)
Project listed date: September 2019
Project: The metabolic repertoire of immune cells – which encompasses metabolic enzymes/pathways, the available nutrient sensors and metabolic checkpoint kinases, and the epigenetic programming of metabolic genes – directly enables and modulates specific immune functions. Capitalizing on a large cohort of patients suffering from rare genetic immunodeficiency that have been whole-genome sequenced, our goal is to delineate the genetic and molecular basis of how cellular metabolism regulates immune-function in human health and disease states. Experimental approaches will involve genomics, molecular biology, cell biology, immunology, and biochemistry with an aim to elucidating mechanisms that lead to new treatment approaches to inborn diseases of immunity.

UK Mentor: Prof. Daniel Hodson
University: Cambridge, Department of Haematology
NIH Mentor:
Project listed date: September 2019 
Project: 

UK Mentor: Dr. Yan Yan Shery Huang
University: Cambridge, Department of Engineering
NIH Mentor: 
Project listed date: September 2019
Project: Establish and implement a glioblastoma-on-a-chip model to study the effect of microenvironments on the tumor progression

UK Mentor: Prof. Andras Lakatos
University: Cambridge, Department of Clinical Neuroscience
NIH Mentor:
Project listed date: September 2019 
Project: Transcriptional and post-transcriptional dysregulation in ALS

UK Mentor: Prof. Matthias Landgraf
University: Cambridge, Department of Zoology
NIH Mentor: Dr. Mihaela Serpe (NICHD)
Project listed date: September 2019
Project: Regulation of neuronal plasticity – integration of synaptic signaling pathways

Neuronal plasticity is fundamental to nervous system development and function. We have recently discovered that reactive oxygen species (ROS), known for their destructive capacity in the ageing or diseased brain, function as second messengers for implementing structural plasticity at synaptic terminals. Moreover, different sources of ROS (cytoplasmic vs mitochondrially generated) regulate genetically distinct aspects of synapse development (growth vs release site number). Do ROS sculpt synapse plasticity in response to the metabolic state of neurons? How does ROS signaling intersect with other signaling pathways regulating synaptic plasticity, such as BMP and Wnt? This project will combine biochemical and genetic approaches with electrophysiology and methods for live and super-resolution imaging to investigate the contribution of various signaling pathways to synapse plasticity. We expect this project to redefine our understanding of how multiple signaling pathways integrate at the synapse to regulate distinct elements of plasticity.

UK Mentor: Prof. Ben Luisi
University: Cambridge, Department of Biochemistry
NIH Mentor: Dr. Gisela Storz (NICHD)
Project listed date: September 2019
Project: The project will use X-ray crystallography, cryoEM, molecular genetics and cellular microscopy to explore how regulatory RNA is used to modulate gene expression with speed and precision in diverse bacteria

UK Mentor: Prof. Stefan Marciniak
University: Cambridge, Cambridge Institute for Medical Research
NIH Mentor: Dr. Craig Blackstone (NINDS)
Project listed date: September 2019
Project: A pathogenic mutant of α1-antitrypsin (Z-α1-antitrypsin) accumulates in the endoplasmic reticulum (ER), disrupting the ER’s tubular structure and interconnectivity as well as increasing the cell’s sensitivity to ER stress.  The efficiency of protein folding, which defends against ER stress, is dependent on diffusion at the nanoscopic scale.  Both folding and diffusion will are affected by ER structure and by the biophysical properties of its luminal environment, such as macromolecular crowding and microviscosity. We have developed Rotor-based Organelle Viscosity Imaging (ROVI) to allow real-time measurement of microviscosity in live cells and have found that Z-α1-antitrypsin forms a hydrogel in the ER that increases local microviscosity while reducing crowding.  This project will investigate chaperone mobility in Z‑α1‑antitrypsin expressing cells and elucidate the mechanisms linking hydrogel formation with increased sensitivity to ER stress, while using advanced super-resolution imaging approaches to assess changes in ER structure.

UK Mentor: Dr. Michal Minczuk
University: Cambridge, MRC Mitochondrial Biology Unit 
NIH Mentor: Dr. Aleksandra Nita-Lazar (NIAID)
Project listed date: September 2019
Project: Studies of the connection between metabolism and innate immunity using mitochondrial mouse mutant models and quantitative proteomics.

UK Mentor: Dr. Sean Munro
University: Cambridge, MRC Lab of Molecular Biology
NIH Mentor: Dr. Justin Taraska (NHLBI)
Project listed date: September 2019
Project: Develop and apply new super-resolution fluorescence and electron microscopy methods to the study of membrane traffic

UK Mentor: Dr. Mike Murphy
University: Cambridge, MRC Mitochondrial Biology Unit
NIH Mentor: Dr. Wei Li (NEI)
Project listed date: September 2019
Project: Explore mitochondrial regulations and their roles in metabolic adaptation during hibernation

UK Mentor: Dr. Luigi G. Occhipinti
University: Cambridge, Department of Engineering
NIH Mentor: 
Project listed date: September 2019
Project: Develop Implantable BIOsensors for the detection of small METAbolites in the inflamed brain.
The project aims to develop and exploit high transconductance organic electrochemical transistor-based bio-sensors and ultra-low power thin-film electronics as emerging ICT tools with perfect fit to the targeted application domain. The proposed sensors and interfaces will provide unprecedented ability to detect and monitor small metabolites both in vitro and in vivo, to map immunometabolism of organs and tissues, and to test new drugs in situ.

UK Mentor: Dr. Timothy O'Leary
University: Cambridge, Department of Engineering
NIH Mentor: Multiple potential NIH collaborators
Project listed date: September 2019
Project: 

  1. Models of ion channel regulation in single cells and small circuits
  2. Modelling robust neuromodulation
  3. Regulation and control of neural activity and circuit dynamics

UK Mentor: Prof. Paul Pharoah
University: Cambridge, Department of Oncology and Public Health and Primary Care
NIH Mentor: Dr. Montserrat Garcia-Closas (NCI)
Project listed date: September 2019
Project: Molecular and somatic genetic profiling of breast tumors in relation to etiology and survival in the Breast Cancer Association Consortium (BCAC)

UK Mentor: Prof. Olivier Restif
University: Cambridge, Department of Veterinary Medicine
NIH Mentor: Dr. Vincent Munster (NIAID)
Project listed date: September 2019
Project: What makes bats good reservoirs of zoonotic viruses?

A growing number of emerging infectious diseases, often with high fatality rates, have been traced back to bats, one of the most diverse and still mysterious order of mammals. Together with Dr Munster, my group is part of an international consortium investigating the association between Henipaviruses and their bat hosts on three continents (https://www.bat1health.org/). This project will combine laboratory work in the NIH Laboratory of Virology with mathematical modelling and bioinformatics at the University of Cambridge. The goal will be to model the interactions between viruses and the immune system of bats, in order to understand the role of within-host dynamics in the maintenance and shedding of zoonotic viruses in bat populations. There may be opportunities to take part in field work in Africa too. Specific research and learning objectives will be tailored to the student’s profile and interests.

UK Mentor: Prof. Steve Russell (Cambridge) & Prof. Stephen Goodwin (Oxford)
University: Cambridge, Department of Genetics & Oxford, Department of Physiology, Anatomy and Genetics
NIH Mentor: Dr. Brian Oliver (NIDDK)
Project listed date: September 2019
Project: Genomic and genetic basis of sex differences in development, physiology, and behavior

UK Mentor: Prof. Ken Smith
University: Cambridge, Department of Medicine
NIH Mentor: Dr. Michael Lenardo (NIAID)
Project listed date: September 2019
Project: Resolving the uncertainty in genetic diagnosis for patients with primary immunodeficiency

We have the largest world-wide collection of patients suffering from rare-inherited immunodeficiency that have been whole-genome sequenced (1500+ cases). Using established analytical expertise the candidate will use novel methods to interrogate and filter potential genetic mutations, we will identify novel candidate genetic loci in patients grouped by disease phenotype or familial relationship. Candidate genetic loci will be investigated using CRISPR-editing of patient derived material (lymphoblastoid, fibroblast and iPS cell lines). Confirmatory studies at mRNA, protein and functional level will be carried out to validate the link between variant and disease.

UK Mentor: Prof. Colin W Taylor
University: Cambridge, Department of Pharmacology
NIH Mentor: Dr. Tamas Balla (NICHD)
Project listed date: September 2019
Project: Close contacts between different membranes are important points of communication between intracellular membranes and between them and the plasma membrane. This project will use high-resolution optical microscopy and novel genetically encoded probes to examine the contribution of these membrane contact sites to spatially organized calcium and phospholipid signalling pathways.

UK Mentor: Dr. Fiona Walter
University: Cambridge, Department of Public Health & Primary Care
NIH Mentor: Multiple potential NIH collaborators
Project listed date: September 2019
Project: Novel approaches to cancer diagnostics in primary care

UK Mentor: Dr. Michelle Linterman
University: Cambridge, Babraham Institute
NIH Mentor: Dr. Pamela Schwartzberg (NIAID) (NHGRI)
Project listed date: September 2019
Project: CRISPr genome editing to understand the germinal centre response upon vaccination throughout the lifespan. At the heart of the immune response to vaccination is the germinal centre (GC) – a dynamic structure that forms in secondary lymphoid tissues after immunisation, and produces long-lived plasma cells, which secrete antibodies that block pathogens from establishing an infection, and memory B cells. A defining property of the GC is the collaboration of multiple cell types: proliferating B cells, T follicular helper cells, T follicular regulatory cells and follicular dendritic cells to produce effector B cells of higher quality. With age, the magnitude of the GC response decreases resulting in impaired production of plasma cells, lower serum antibody levels and consequently, decreased protection against subsequent infection. This project aims to identify and characterise molecules that are important for germinal centre biology in the context of normal function and in ageing, using CRISPR-mediated mutagenesis to screen for novel players in T follicular helper cells. We will take advantage of mouse models and human cohorts to generate mechanistic understanding of the GC response that is of direct relevance to human biology.

UK Mentor: Dr. Jonathan Heeney
University: Cambridge, Lab of Viral Zoonotics, Vet School
NIH Mentor: Dr Genoveffa (Veffa) Franchini (AMVRS,CCR,NCI,NIH)
Project listed date: September 2019
Project: We have several lines of research that accommodate excellent PhD candidates. These revolve around the theme of RNA viral pathogens, antibodies/B-cell responses and immunodefifiencies.
The 1st involves understanding Immune Correlates of protective immunity, specifically which types of B-cell response and their fine specificities are important for protection against specific RNA viral pathogens (RNA viruses from HIV, HCV to Ebola) how B-cell responses to correlate with protection by vaccines to specific pathogens. The 2nd project involves using broadly neutralizing monoclonal antibodies to develop improved and novel vaccines against notoriously variable viruses. The 3rd project involves understanding how the resident virome in primary, acquired or induced immunodeficies leads to chronic immune activation and poor prognosis, with an emphasis on mucosal immunity.

UK Mentor: Prof. Julian Parkhill
University: Cambridge, Veterinary Medicine
NIH Mentor: Unspecified
Project listed date: September 2019
Project: Transmission of bacteria and antimicrobial resistance determinants between and among animals and humans.
We are interested in the transmission of bacterial pathogens and AMR determinants at multiple scales from the within-hospital level to global networks. Projects are possible on many large-scale datasets, primarily using population genomic and phylogenetic approaches to investigate these processes.

UK Mentor: Prof. Eamonn Maher
University: Cambridge, Medical Genetics
NIH Mentor: Dr. Ping Zhuang (NICH)
Project listed date: September 2019
Project: Genomic and epigenomic studies into the mechanisms of tumourigenesis in individuals with inherited predisposition to neuroendocrine tumour syndromes 

UK Mentor: Prof. Manohar Bance
University: Cambridge, Clinical Neuroscience
NIH Mentor: Unspecified
Project listed date: September 2019
Project: To develop “organ on chip” model of the cochlea for rapid drug assay, and to test new generations of cochlear implants.
We have an interdisciplinary program with biomaterials, clinicians, surgeons, electrical engineers and chemical engineers to 3D fabricate cochleas with microanatomy similar to living cochleas, embedded with sensors that can sense current spread from cochlear implants, or ion gradients from various inner ear cell types that can generate them. Our goal is to develop these types of constructs, seed them with 3D cultures of various  inner ear cell types and examine how cochlear implants can activate auditory neurones, or how regeneration or pharmacologic support for hearing loss can be developed.  his is in order to develop the next generation of inner ear hearing loss therapies.

UK Mentor: Dr. Martin Welch
University: Cambridge, Biochemistry
NIH Mentor: Unspecified
Project listed date: September 2019
Project: The opportunistic human pathogen, Pseudomonas aeruginosa, is a commonly-found inhabitant in the airways of patients with chronic respiratory ailments such as COPD and cystic fibrosis (CF). Short chain fatty acids (SCFAs) such as acetate and propionate accumulate to high levels in the airways of these patients. In mutants of P. aeruginosa that are unable to catabolise SCFAs, these compounds are toxic and lead to cessation of growth. In this project, we aim to use fragment-based drug discovery to identify inhibitors of the key enzymes involved in propionate catabolism (PrpB and PrpC) and acetate assimilation (AceA). We have recently solved the x-ray crystal structure of each enzyme, and are supported by the Diamond Light Source to initiate a FBDD programme. Challenges will be to identify high affinity binders with specificity for the intended targets. Cell permeability and efflux of the “hits” will need to be investigated, as will “off target” effects, cytotoxicity to mammalian cells, and likely resistance mechanisms. Species specificity of inhibition will be examined in an in vitro polymicrobial system recently developed in the lab.   

UK Mentor: Prof. Janet Kumita
University: Cambridge, Chemistry
NIH Mentor: Unspecified
Project listed date: September 2019
Project: Dissecting the relationship between amyloid structures and cellular dysfunction in human diseases

Aggregation in vivo is associated with a wide range of human disorders including Parkinson’s disease, systemic amyloidosis and motor neurone disease. As the process of amyloid formation results in the population of a highly heterogeneous array of different protein conformers, it is extremely difficult to resolve how specific misfolded protein states elicit detrimental cellular responses. We aim to define the structural attributes of these elusive species and to determine their influence on cellular trafficking, homeostasis and cell-to-cell transfer processes, all factors that are crucial in disease progression.

Key areas of interest include:
1) Probing how globular proteins form amyloid fibrils
2) How accessory proteins, such as extracellular chaperones, modulate amyloid formation and how this is related to disease pathology
3) The impact of post-translational modifications on amyloid fibril formation
4) How changes in the cellular quality control mechanisms impact on amyloid fibril formation

UK Mentor: Dr. Mara Lawniczak
University: Sanger Institute
NIH Mentor: Dr. Adam Phillippy (NHGRI)
Project listed date: September 2019
Project: Population genomic approaches across diverse species have traditionally used short read sequence data to investigate population structure and signatures of selection. In the recent past, long reads are more traditionally used to build reference genomes to which the short read data can be aligned and evaluated. However, the cost of long read sequencing as well as the DNA input required to generate high quality long read data is dropping rapidly. We foresee a future where population genomics transitions to long read data.

Using these emerging technologies, this project will begin to evaluate what new insights are gained for the Anopheles gambiae species complex, a set of mosquito species famous as the vector of malaria and known to exhibit porous species boundaries and abundant structural variation.  We anticipate that long-read approaches for haplotype phasing and structural variant discovery will enable much clearer resolution of gene flow within species, introgression between species, and alleles under directional or balancing selection.  Insights gained from this project are likely to influence approaches taken for other species that are known to have similar complexities (e.g., Heliconius butterflies, African cichlid fishes).

This project will involve developing and applying new computational methods for analysing long-read sequencing data in an Anopheles population genomics context. The collaborating laboratories at the Sanger Institute and NHGRI are experts in these respective areas and well-suited to provide the appropriate mentorship.

UK Mentor: Prof. Zoe Kourtzi
University: Cambridge, Psychology
NIH Mentor: Potential collaboration with Peter Bandettini Laboratory of Brain and Cognition (NIMH)
Project listed date: September 2019
Project: Ultra-high field imaging of adaptive brain circuits
The human’s brain capacity for sensory plasticity has been studied mainly in the context of neurodevelopment (i.e. critical periods) and pathology (e.g. amblyopia) with interventional approaches (e.g. sensory deprivation) that result in drastic brain re-organisation. Yet, understanding the brain plasticity mechanisms that mediate subtler changes in perceptual judgments through shorter-term experience and training remains a challenge. 
This project focuses on the brains ability to improve perceptual skills at the core of visual recognition through training; that is, the ability to detect the features of an object from cluttered backgrounds and discriminate whether they belong to the same or different objects. Learning and experience have been suggested to facilitate this ability to translate complex patterns of visual information into perceptual decisions. We will exploit methodological advances in high-field (7T) brain imaging to investigate functional and neurochemical brain plasticity mechanisms at finer-scale. We will test the hypothesis that perceptual learning is implemented by feedback and inhibitory mechanisms that re-weight sensory information across stages of processing (from early to higher visual cortex). In particular, the high resolution of 7T imaging allows us to measure functional signals in different cortical layers. We will test whether learning alters fMRI activation patters in deep—rather than middle—layers in the visual cortex, consistent with feedback processing. Further, advances in MR Spectroscopy enable us to test the role of GABA—the primary inhibitory neurotransmitter for brain plasticity—in perceptual learning. We will test whether learning-dependent changes in GABA relate to changes in functional brain activity and improved behavioural performance in perceptual tasks. Investigating these core mechanisms of brain plasticity will advance our understanding of how the brain optimises its capacity to support adaptive behaviour through learning and experience.

UK Mentor: Prof. Richard Henson
University: Cambridge, MRC Cognition and Brain Sciences Unit & Department of Psychiatry
NIH Mentor: Dr. Alex Martin (NIMH)
Project listed date: September 2019
Project: Neural bases of repetition priming.
Repetition priming (RP) is a basic form of memory, whereby prior exposure to a stimulus facilitates or biases subsequent responses to that stimulus. From a neuropsychological perspective, RP is interesting because it can occur without awareness, and despite the damage to the medial temporal lobe (MTL) system that produces amnesia. Many functional neuroimaging studies using fMRI and MEG/EEG have investigated the brain regions and neuronal dynamics associated with RP. However, the results are complex, depending on several important variables, and suggesting multiple underlying neural mechanisms. Recent computational models provide some insight, and the proposed project will extend these models to a broader range of neuroimaging data, including existing data from intracranial recording in human and non-human primates.

UK Mentor: Prof Adrian Liston
University: Babraham Institute
NIH Mentor: Unspecified
Project listed date: September 2019
Project: Tumour growth is intimately linked to the infiltration of leukocytes (immune cells). Recruitment of suppressive leukocytes can promote angiogenesis and tissue remodelling, while repulsion of pro-inflammatory leukocytes is required to prevent tumour rejection. To date, this process has been studied in a hypothesis-directed manner, identifying a role for gene X in leukocyte subset Y. Here we will use new genome engineering approaches to simultaneously test the impact of every known migration-associated molecule in every infiltrating leukocyte subset, in order to reach a truly comprehensive understanding of the genes controlling the entry of each cell type into the tumours.

This project is based around the cutting-edge “Pro-code” technology. “Pro-codes” allows up to 400 lentiviruses to be built, each with a unique protein-based barcode. 400 unique CrispR guideRNAs can be built into a barcoded lentivirus library, covering every known migration-associated gene (chemokine receptors, integrins, adhesion molecules, chemotactic receptors, matrix metalloproteases, etc). Transfection of inducible Cas9-expressing bone-marrow stem cells with the ProCode library creates a mouse where the immune system is a mosaic of 400 different knockout lines. Through ultra-high parameter single cell cytometry, we can compare leukocytes that stay in circulation, migrate to healthy tissue or enter tumour tissues. Relative enrichment and depletion of each barcode in each leukocyte subset provides a comprehensive genetic map of leukocyte entry into tumours.

UK Mentor: Dr. Chris Rodgers
University: Cambridge, Wolfson Brain Imaging Centre, Dept of Clinical Neurosciences
NIH Mentor: No
Project listed date: November 2019
Project: Ultra-High Field (7T) Magnetic Resonance Imaging (MRI) Development
I founded a new ultra-high field (7T) MRI physics group in Cambridge in autumn 2017. We develop cutting-edge methods for studying the human brain and body using Cambridge’s state-of-the-art Siemens Terra 7T MRI scanner. My group have active collaborations with clinicians in clinical neurosciences, psychiatry, oncology, and cardiology (Papworth), and with experts in cognitive neuroscience. I welcome PhD students to join the group. The following are areas of strong interest from our community, which would be suitable to develop a PhD project in discussion with me.


(i) Developing new spectroscopic imaging pulse sequences to map neurochemical profiles across the whole brain in a single scan. We have hardware available to apply these methods to study metabolites containing 1H (e.g. NAA, creatine, GABA, GSH) or 31P (e.g. PCr, ATP, in vivo pH mapping) or 13C (e.g. labelled glucose or succinate).
(ii) Developing new methods for neuroimaging, particularly for imaging blood flow in small vessel disease, or for rapid, motion-corrected fMRI in deep brain nuclei.
(iii) Developing new metabolic imaging methods for use in the human body. These would use a new multinuclear (1H and 31P) whole-body coil being built for me by Tesla Dynamic Coils (Netherlands). This could be developed in collaboration with colleagues at Papworth and Radiology for studies in the heart.
(iv) Imaging of metabolism by 2H deuterium metabolic imaging (DMI). This is a promising new technique that may UK


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