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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)

NIH Mentor: Dr. Sam M. Mbulaiteye (NCI/DCEG)
UK Mentor: Prof. Ana Schuh
University: Oxford, Department of Oncology
Project listed date: September 2019
Project: The Epidemiology of Burkitt lymphoma in East African children and minors (EMBLEM) is a research study sponsored by the Intramural Research program of the National Cancer Institute under Protocol #: 10-C-N133 during 2010-2016 to comprehensively investigate infections, immunological, and genetic risk factors of Burkitt lymphoma (BL).

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: September 2019
Project: Elucidate basic mechanisms of HIV replication at the molecular level, with an emphasis on the late states of the virus replication cycle.

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: Conprehensive 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: Explore mitochondrial regulations and their roles in metabolic adaptation during 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: September 2019
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. Folma Buss
University: Cambridge, Cambridge Institute for Medical Research
Project listed date: September 2019
Project: This project will involve the study of myosin function in vitro and in cells.  Myosins are a superfamily of molecular motors which carry out many functions in cells.  The aim of this partnership would be to combine the strong expertise of the Buss lab in studies of myosins in cells with the in vitro biochemical and biophysical approaches used in the Sellers lab.

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: 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.

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: September 2019
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. 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: Stefan Muljo (NIAID)
UK mentor: Dr. Anindita Roy 
University: Oxford, Department of Paediatrics
Project listed date: September 2019
Project: Elucidating fetal haematopoiesis in mouse and human

Haematopoiesis is a finely tuned process by which mature blood cells of multiple lineages are constantly generated throughout life from haematopoietic stem cells. In humans, definitive haematopoiesis commences in the fetal liver (FL) at around five weeks of gestation, and remains the main site of haematopoiesis throughout fetal life. Haematopoiesis in the bone marrow (BM) starts around 11-12 weeks of gestation, but does not take over as the primary site of haematopoiesis until just after birth. Recent evidence suggests that fetal haematopoiesis is distinct from postnatal haematopoiesis 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 haematopoiesis in the human setting, remains to be determined. We, and others have begun to investigate unique features of human fetal haematopoiesis and this project will determine fetal specific programmes that change through ontogeny. Studying haematopoiesis 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. It may also have therapeutic implications in the use of haematopoietic stem cells from donors of different ages as these cells vary in their composition and differentiation potential, which may depend on the physiological processes or demands of that particular developmental stage, and/or in response to specific microenvironmental cues.  

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. 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.

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. 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: September 2019
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: September 2019
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: September 2019
Project: Exploration of mechanisms underlying heterogeneity of response in personalized cancer immunotherapy by using machine-learning techniques.

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. Colin Goding
University: Oxford, Ludwig Institute for Cancer Research
NIH Mentor: Dr. Kapil Bharti (NEI)
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.

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. Jane Green
University: Oxford, Nuffield Department of Population Health
NIH Mentor: Dr. Amy Berrington de Gonzalez (NCI)
Project listed date: September 2019
Project: Diet and brain tumors in the UK million women study and the US NIH-AARP diet and health study

UK Mentor: Dr. Timothy Hinks
University: Oxford, Nuffield Department of Medicine
NIH Mentor:
Project listed date: September 2019
Project: Mucosal immunology of non-typeable Haemophilus influenzae in lower airways inflammation

Aim: to elucidate the mucosal immunological mechanisms underlying the dramatic recent observation that macrolide antibiotics reduce exacerbations in asthma.

Our group investigate the cellular immunology of asthma: the world’s commonest chronic lung disease, affecting 350 million people worldwide. We are applying novel murine models of persistent bacterial infection of the airway mucosa with major human airway pathogens including non-typeable Haemophilus influenzae (NTHi) to dissect the cellular immune response driving steroid-resistant airways inflammation in some phenotypes of asthma. We have a specific interest in mucosal T cells including MAIT cells and collaborate with leading UK T cell biologist Paul Klenerman and with the International Mouse Phenotyping Consortium at Harwell MRC.

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. Richard Maude
University: Oxford, Nuffield Department of Medicine
NIH Mentor: Dr. Stefan Jaeger (NLM)
Project listed date: September 2019
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. 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: 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: October 2019
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. Laura Parkkinen
University: Oxford, Nuffield Department of Medicine
NIH Mentor: (TBD)
Project listed date: October 2019
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. 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. Mark Howarth
University: Oxford, Biochemistry
NIH Mentor: No
Project listed date: October 2019
Project: Protein superglues: design, evolution and application in the area of vaccines, cancer therapeutics or diagnostic imaging.

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.

UK Mentor: Prof.Ana Domingos
University: Oxford, Department of Physiology, Anatomy & Genetics
NIH Mentor: (TBD)
Project listed date: November 2019
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
 

Cambridge

UK Mentor: Prof. Chris Abell
University: Cambridge, Department of Chemistry
NIH Mentor: Dr. Clif Barry (NIAID)
Project listed date: September 2019
Project: Mycobacterium tuberculosis to provide chemical validation of a target prior to therapeutic development

The increasing prevalence of drug-resistant microorganisms worldwide and the shortage of novel antimicrobial chemotherapeutics in the pipeline places our capacity to treat infectious diseases, such as Tuberculosis, under serious threat. Antimicrobial chemotherapies with novel modes of action are desperately needed. In multiple pathogenic microorganisms, the conserved biosynthesis pathway of Coenzyme A (CoA), has been shown to be an essential enzyme cofactor. Using fragment-based approaches, pioneered in Cambridge, the aim will be to develop a series of highly potent inhibitors of the most vulnerable enzyme targets in the bacterial CoA biosynthesis pathway of Mycobacterium tuberculosis (Mtb). The aim will be to focus efforts in confirming that tuberculosis (TB) can be combatted with small molecule CoA pathway inhibitors.

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: Dr. Gonçalo Bernardes
University: Cambridge, Department of Chemistry
NIH Mentor: Multiple potential NIH collaborators
Project listed date: September 2019
Project: Reversible Covalently Binding PROTACs Technology for Target Protein Degradation
Drug development research typically focus on small molecules to inhibit the activity of proteins that promote cell proliferation. The high concentrations of the small molecule required for efficient target inhibition often lead to off-target effects. Recently, a proteolysis targeting chimera (PROTACs) approach has received much attention for therapeutic intervention by means of degradation of disease-causing proteins. However, and despite the high affinity and high specificity of PROTACs, they often suffer from poor stability, cell permeability and more importantly lack of cell specificity. In this project, we propose a novel strategy for the rational design and synthesis of reversible covalently binding PROTACs (RECOBIN-PROTACs) based on the proximity labeling. A RECOBIN-PROTAC molecule consists of target protein ligand, E3 ligase ligand and a chemoselective functional group connected through flexible linkers. The chemoselective functional group forms reversible covalent modification with proximal lysine residue of a target protein or the E3 ligase. This proximity labeling enhances the binding affinity of the ligands to the targets, stabilizing protein-protein interactions in ternary complex formation. The library of RECOBIN-PROTACs will be tested on AML cell lines to find most efficient degraders. The most efficient RECOBIN-PROTACs will be conjugated site-selectively to a tumour-targeting antibody to generate stable RECOBIN-PROTAC-Antibody Conjugates. These conjugates selectively release the active RECOBIN-PROTAC inside the target cells upon protease cleavage. The features of RECOBIN-PROTACs technology will bring new modalities in therapies and drug discovery.

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. Clare Bryant
University: Cambridge, Department of Veterinary Medicine
NIH Mentor: Dr. Aleksandra Nita-Lazar (NIAID)
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.

UK Mentor: Prof. Clare Bryant
University: Cambridge, Department of Veterinary Medicine
NIH Mentor: Dr. Raphaela Goldbach-Mansky (NIAID)
Project listed date: September 2019
Project: How do disease-inducing mutations affect inflammasome formation?
Inflammasomes are large macromolecular complexes which in its mots minimal form is composed of a receptor (nlr), an adaptor protein (ASC) and an effector protein (caspase 1).  It is highly likely inflammasomes are responsible for driving sustained inflammation in many chronic inflammatory diseases.  The net effect of inflammasome activation is to process pro-inflammatory cytokines such as interleukin 1b and interleukin 18 as well as to drive cellular death through the effector protein gasdermin D.  Our work, using super resolution microscopy, along with studies from other researchers suggest that the inflammasome can contain different receptor and/or effector proteins to tailor a specific inflammatory response depending upon how the stimulus received by the cell.  Our proteomic analysis suggests that during inflammasome activation a subset inflammatory proteins are released from cells (danger associated molecular patterns (DAMPs)) which could play an as yet uncharacterised roles in driving inflammatory disease and therefore provide novel drug development targets. 
A subset of rare autoinflammatory diseases are caused by gain-of-function (GoF) mutations in inflammasome related genes such as nlrp3 and nlrc4.  Why inflammasomes are dysfunctional in these patients, which cell types are central to the disease syndrome and the resulting inflammation-induced organ damage remains to be understood.  It is likely that the GoF mutations alter the way in which an inflammasome is formed and the DAMPs released will influence the type of inflammation induced.  We have generated human macrophage models where the GoF mutations have been introduced and candidate DAMP genes removed by CRISPR/Cas9 gene editing.  We have also tagged the endogenous nlrs with fluorescent tags.    In this project will use cutting edge imaging techniques (super resolution microscopy, single molecule fluorescence, cell signaling and CRISPR/Cas9 gene editing) and cell signalling assays in our different macrophage models (gene edited THP1 cells, iPSC-derived cell lines and primary cells from patients with GoF mutations).  The project will to determine how inflammasome dysregulation occurs and the consequences of this for the host inflammatory response. 

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: Prof. Anthony Coyne
University: Cambridge, Department of Chemistry
NIH Mentor: 
Project listed date: September 2019
Project: 

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. Julian Griffin
University: Cambridge, Department of Biochemistry
NIH Mentor: 
Project listed date: September 2019
Project: Gestational diabetes mellitus (GDM) is diabetes that arises during pregnancy which is not overt diabetes, and affects 2-6% of live births in Europe. GDM is caused by hormonal changes during pregnancy inducing insulin resistance, and can in turn increase the risk of pre-eclampsia and fetal abnormalities. While mothers return to normal insulin sensitivity post-delivery, GDM is a significant risk factor for the future development of type 2 diabetes. Despite a general understanding of the pathology of GDM, it is still not understood why women develop GDM on an individual basis. This study aims to define the metabolic changes that accompany GDM using liquid chromatography mass spectrometry to analyse a wide range of metabolites and lipids. Women will be recruited during the normal screening process for GDM as defined by the American Diabetes Association. We will collect blood plasma from 500 volunteers with and without GDM following a non-fasting 50 g glucose challenge at 24-28 weeks (first stage of screening). To place metabolic differences detected in mechanistic context we will also examine 20 women with and without GDM during an oral glucose tolerance test both during pregnancy (second stage of screening used to confirm diagnosis of GDM) and post-delivery (when normal insulin sensitivity usually returns). The data will be examined using multivariate statistics to examine cross-correlations between the different screens and the collected clinical data. In turn, modelling these results will provide a greater understanding of the metabolic deficits that are induced by GDM.

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: Prof. Rita Horvath
University: Cambridge, Department of Clinical Neurosciences
NIH Mentor: Dr. Carsten Bӧnnemann (NINDS)
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.

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: Prof. Patrick Maxwell
University: Cambridge, Institute for Medical Research
NIH Mentor: Dr. Susan Pierce
Project listed date: September 2019
Project: The role of the hypoxia pathway in the survival of long-lived plasma cells and memory B- cells

Antibody production is an essential arm of the adaptive immune system providing both immediate and long-term protection against infection. 
Long-lived plasma cells reside in specialised niches in the bone marrow and are responsible for secreting high antibody titres, providing protection following exposure to antigen or immunisation. The bone marrow is a hypoxic environment suggesting that the hypoxia pathway may be essential for the proliferation, function and survival of plasma cells. However, the role of the hypoxia pathway in plasma cells is unknown. This translational project will utilise transgenic mouse models, human tissues, imaging and sequencing techniques to address how hypoxia influences plasma cells. We expect the project to provide new insight into antibody responses that will have important implications in a range of immunological settings including vaccine response, transplant rejection, autoimmunity and cancer.

UK Mentor: Dr. Martin Miller
University: Cambridge, Cancer Research UK Cambridge Institute
NIH Mentor: Dr. Grégoire Altan-Bonnet (NCI)
Project listed date: September 2019
Project: Modeling tumor-immune interactions at the systemic, microenvironmental and cellular levels

Our understanding of how cancer cells cooperate to evade anti-tumor immune control is limited.  We hypothesize that different clones within the tumor cooperate and create an immunosuppressive and pro-tumorigenic microenvironments.  This PhD project aims to uncover such mechanisms of tumor immune escape by modelling interactions between tumor cells and immune cells at a multi-scale level.  Using a combination of mass cytometry, novel cell-selective labeling methods, genomics and mouse tumor modeling, we will explore how tumor clonal heterogeneity modulates tumor-infiltrating immune cells and create unique tumor microenvironments during in vivo tumor progression. The interactions between tumor clones and immune cells will be resolved in a spatial context in the local tumor microenvironment using imaging mass cytometry of individual cells in tumor tissue slides. The interactions between the tumor and the immune system will be resolved at the systemic level using single cell mass cytometry analysis of circulating immune cells in the blood of tumor-bearing mice. Mathematical modeling of tumor-immune interactions ranging from the single cell, to the microenvironmental, to the systemic levels will reveal mechanisms of tumor-mediated immunosuppression which will be further investigated in follow-up experiments. The outcome will be a quantitative framework to interpret the balance between inflammation and tolerance within the tumor microenvironment.

This project directly synergizes between the two groups with the Miller group specializing in dissecting the role of tumor-immune interactions in the tumor microenvironment and with the Altan-Bonnet having a long-standing interest in expanding quantitative models in immunology, e.g. as it pertains to modeling immunotherapeutic outcomes. The PIs share common scientific directions based on discussions within the program for Computational Biology at Memorial Sloan Kettering Cancer Center (from 2006 until 2016 for Altan-Bonnet, from 2008 until 2014 for Miller).

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. Lalita Ramakrishnan
University: Cambridge, Department of Medicine
NIH Mentor: Dr. Steve Holland (NIAID)
Project listed date: September 2019
Project: We have developed the zebrafish as a model for tuberculosis immunopathogenesis, exploiting its genetic tractability and the optical transparency of the developing animal.  Host-pathogen interactions can be monitored live in exquisite detail after manipulation of host and pathogen genes.  The use of this model has enabled  us to make surprising discoveries about TB pathogenesis with immediate clinical implications.  Two of our findings are now in the clinical arena.
In the context of this program, Steve Holland and I would like to take the converse approach.  We would like to identify human genetic mutations that are associated with human susceptibility to TB or to atypical mycobacteria. These can be rare or common.  We propose to create these mutations in the zebrafish fish and determine the basis of the susceptibility in molecular and cellular detail.  These findings have the potential to understand the pathogenesis of TB and atypical mycobacterioses as well as other inflammatory diseases.  Based on our prior experience, we can expect to shed light on fundamental immunological networks and identify completely new treatment possibilities for these often intractable conditions.

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. David Ron
University: Cambridge Institute for Medical Research 
NIH Mentor:
Project listed date: September 2019
Project: 

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: Dr. Elisabetta Spagone
University: Cambridge, Department of Chemistry
NIH Mentor: 
Project listed date: September 2019
Project: 

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. Yorgo Modis
University: Cambridge, Medicine
NIH Mentor: Dr. Joseph Marcotrigiano (NIAID)
Project listed date: September 2019
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. This is potentially dangerous for the cell because interferon is toxic and the cytosol is full of endogenous RNAs some of which are chemically similar to viral RNAs. With gain of function mutations in MDA5, endogenous RNA can activate signaling, causing autoimmune diseases including Singleton-Merten syndrome and Aicardi-Goutières syndrome. So how does MDA5 efficiently distinguish between viral and endogenous RNA? Last year, we discovered that ATP hydrolysis by MDA5 is coupled to conformational changes in the filaments. This led us to proposed that the ATPase cycle encodes a mechanical proofreading function by challenging the interactions between MDA5 and RNA such that only RNAs with virus-specific properties remain associate long enough to activate signaling (https://www.ncbi.nlm.nih.gov/pubmed/30449722). However, fundamental questions remain regarding this hypothesis. Which physicochemical properties in RNA does MDA5 recognize? How are these properties affected by the extensive chemical modifications applied to RNA? And how do disease-associated mutations affect recognition?

We will use a combination of cryoEM, biochemical assays and cell-based signaling assays to determine how specific chemical RNA modifications (including m6A, 5mC and A-to-I deamination) affect MDA5-RNA recognition. We will also use an RNA translocation assay to determine whether ATP hydrolysis leads to translocation of MDA5 along RNA, allowing it to displace viral proteins from RNA, which would represent a new antiviral activity. We will also assess how the RNA binding and cell signaling activities of MDA5 are affected by various disease-associated mutations in MDA5. In the longer term, this work may help identify MDA5 agonists and a new type of immunotherapeutic.

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. Rita Horvath
University: Cambridge, Clinical Neurosciences
NIH Mentor: Dr. Carsten Bӧnnemann (NINDS)
Project listed date: September 2019
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: 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: Prof. Amanda Sferruzzi-Perri
University: Cambridge, Physiology, Development and Neuroscience
NIH Mentor: Unspecified
Project listed date: September 2019
Project: Placental hormones and pregnancy health in obese mothers

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 sequencing and histological methods to characterise the effect of obesity on the placental production of hormones with metabolic effects. It will also use metabolic, molecular 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.

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: Dr. Helle Jorgensen
University: Cambridge, Medicine
NIH Mentor: Unspecified
Project listed date: September 2019
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.

UK Mentor: Dr. JL Gallop
University: Gurdon Institute and Department of Biochemistry
NIH Mentor: Dr. James Sellers (NHLBI)
Project listed date: September 2019
Project: Filopodia are finger-like actin-rich protrusions from cells involved in axon guidance, synaptogenesis, cell migration, cancer and pathogen infection, amongst other functions, and are important, though little understood structures in cell biology. This new collaboration between Dr. Gallop and Dr. Sellers will use a cell-free system of filopodia formation combined with biochemistry and advanced microscopy to study the role of myosins in the assembly and dynamics of filopodia.

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: Prof. Ross Waller
University: Cambridge, Biochemistry
NIH Mentor: Dr. Michael Grigg
Project listed date: September 2019
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.


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This Page Last Updated on November 5, 2019
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