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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.

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. Christian Abnet (NCI/DCEG)
UK mentor: Prof. Rebecca Fitzgerald
University: CambridgeMRC Cancer Unit
Project: Genetics of squamous cell carcinoma - identifying high risk groups

NIH Mentor: Dr. Grégoire Altan-Bonnet (NCI)
UK Mentor: Dr. Martin Miller
University: Cambridge, Cancer Research UK Cambridge Institute
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).

NIH mentor: Dr. Amy Berrington de Gonzalez (NCI)
UK mentor: 
University:
Project: 

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

NIH Mentor: Dr. Tom Misteli (NCI/CCR)
UK Mentor: Prof. Yorgo Modis
University: Cambridge, Department of Medicine
Project: Molecular mechanism of transgene silencing by the Human Silencing Hub (HUSH) and MORC2

NIH mentor: Dr. Ludmila Prokunina-Olsson (NCI)
UK mentor:
University:
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: 

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

National Center for Advancing Translational Sciences (NCATS)

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

National Center for Complementary and Integrative Health (NCCIH)

NIH mentor: Dr. Lauren Atlas (NCCIH/NIDA)
UK mentor:
University:
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: 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: 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: Explore mitochondrial regulations and their roles in metabolic adaptation during hibernation.

National Heart, Lung, and Blood Institute (NHLBI)

NIH Mentor: Dr. Herb Geller (NHLBI)
UK Mentor: Prof. Keith Martin
University: Cambridge, Department of Clinical Neurosciences (Ophthalmology)
Project: The project will develop new methods to stimulate axon regeneration from the retina to the brain. The first method will be based on expressing integrins and integrin activators in ganglion cells, which has been dramatically successful in the spinal cord. The second method will be to activate signalling via phosphatidylinositols to stimulate axonal transport and motility. The project will also examine guidance of regenerating axons. Co-supervised by Professors James Fawcett and Keith Martin.

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

NIH mentor: Dr. Chris Hourigan (NHLBI)
UK mentor: Prof. Chris O'Callaghan
University: Oxford, Nuffield Department of Medicine
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: Investigating the impact of dendritic cell-T cell interactions on autocrine complement activation in CD4 T cells.

Summary: 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.

NIH Mentor: Dr. Ken Olivier (NHLBI) & Dr. Steve Holland (NIAID) 
UK Mentor: Prof. Andres Floto
University: CambridgeDepartment of Medicine
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: 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: Develop and apply new super-resolution fluorescence and electron microscopy methods to the study of membrane traffic.

National Human Genome Research Institute (NHGRI)

NIH mentor: Dr. Philip Shaw (NHGRI)
UK mentor: Collaborators at both universities
University:
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: Prof. Chris Abell
University: Cambridge, Department of Chemistry
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.

NIH mentor: Dr. Bibiana Bielekova (NIAID)
UK mentor:
University:
Project: Development of cell-specific or process-specific biomarkers for CNS diseases.

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

NIH mentor: Dr. Michael Lenardo (NIAID)
UK mentor: Prof. Christoph Hess 
University: Cambridge, Department of Medicine
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. Michael Lenardo (NIAID)
UK Mentor: Prof. Ken Smith
University: Cambridge, Department of Medicine
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.

NIH Mentor: Dr. Vincent Munster (NIAID)
UK Mentor: Prof. Olivier Restif
University: Cambridge, Department of Veterinary Medicine
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: 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. Susan Pierce (NIAID)
UK Mentor: 
University: 
Project:

NIH mentor: Dr. Thomas Quinn (NIAID)
UK mentor: Prof. Christophe Fraser
University: Oxford, Big Data Institute
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: 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. Jonathan Yewdell (NIAID)
UK Mentor: Prof. Ervin Fodor
University: Oxford, Dunn School of Pathology
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: 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: Understanding of the mechanisms through which CD4 T helper cells and innate lyphoid cells acquire their specific protective/tissue damaging effects.

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: 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: Identifying genetic causes of neurometabolic disorders and develop gene therapy treatments for these diseases

NIH Mentor: Dr. Karel Pacak (NICHD)
UK Mentor: 
University: 
Project:Undertake genomic and epigenomic studies into the mechanisms of tumourigenesis in individuals with inherited predisposition to neuroendocrine tumour syndromes (phaeochromocytoma/paraganglioma) associated with renal cell carcinoma to study their commonalities as well as differences. Such discoveries can lead to understanding of developmental and other mechanisms in tumours 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 tumour-specific as well as tumour-non-specific targets.

NIH Mentor: Dr. Mihaela Serpe (NICHD)
UK Mentor: Prof. Matthias Landgraf
University: Cambridge, Department of Zoology
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: 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.

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

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

NIH Mentor: Dr. Michael Krashes (NIDDK)
UK Mentor: Dr. Mark Evans
University: Cambridge, Department of Medicine
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: 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.

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: 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: 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: Combined Computational-Experimental Approaches to Predict Acute Systemic Toxicity.

National Institute of Mental Health (NIMH)

NIH mentor: Dr. Victor Pike (NIMH)
UK mentor: Prof. Franklin Aigbirhio (Cambridge); Prof. Véronique Gouverneur (Oxford)
University: Cambridge & Oxford
Project: Invent and implement new radioactive probes for imaging specific molecular targets in animal and human brain with positron emission tomography.

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: 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: 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: Understand the disease mechanism and potential treatments of the polyglutamine expansion diseases that include Huntington's disease and muscular dystrophy.

NIH mentor: Dr. Avindra Nath (NINDS)
UK mentor:  Prof. Peijun Zhang
University: Oxford, Nuffield Department of Clinical Medicine
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: 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: The tubulin code in health and disease

NIH mentor: Dr. Kareem Zaghloul (NINDS)
UK mentor:
University:
Project: Exploring the neural mechanisms underlying human cognitive function using intracranial recordings captured from neurosurgical patients

National Library of Medicine (NLM)

NIH mentor: Dr. Stefan Jaeger (NLM)
UK mentor: Prof. Richard Maude
University: Oxford, Nuffield Department of Medicine
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.

Oxford

UK Mentor: Prof. Ervin Fodor
University: Oxford, Dunn School of Pathology
NIH Mentor: Dr. Jonathan Yewdell (NIAID)
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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: The tubulin code in health and disease

UK Mentor: Prof. Trudie Lang
University: Oxford, Nuffield Department of Medicine
NIH Mentor: 
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: 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: 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: 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: 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: 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: Understand the disease mechanism and potential treatments of the polyglutamine expansion diseases that include Huntington's disease and muscular dystrophy

UK Mentor: Prof. Peijun Zhang
University: Oxford, Nuffield Department of Clinical Medicine
NIH Mentor: Dr. Avindra Nath (NINDS)
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: 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: 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. 

Cambridge

UK Mentor: Prof. Chris Abell
University: Cambridge, Department of Chemistry
NIH Mentor: Dr. Clif Barry (NIAID)
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. Frank Aigbirhio
University: Cambridge, Department of Neuroscience
NIH Mentor: Dr. Victor Pike (NIMH)
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: Radiology - Prostate Cancer Imaging

UK Mentor: Prof. Andreas Bender
University: Cambridge, Department of Chemistry
NIH Mentor: Dr. Richard Eastman & Dr. Rajarshi Guha (NCATS)
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: 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: To explore a new target that is overexpressed in the new blood vessels in solid cancers to 
deliver potent drugs into the tumour neovasculature. This project involves antibody design and 
engineering, immunohistochemistry of cancer samples from patients, advanced antibody 
conjugation strategies, cancer chemical biology and therapeutic efficacy in vivo.

UK Mentor: Prof. Guy Brown
University: Cambridge, Department of Biochemistry
NIH Mentor:
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: 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: How do disease-inducing mutations affect inflammasome formation and activation?

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

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

UK Mentor: Dr. Patrick Chinnery
University: CambridgeDepartment of Clinical Neurosciences
NIH Mentor:
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: 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: 

UK Mentor: Dr. Mark Evans
University: Cambridge, Department of Medicine
NIH Mentor: Dr. Michael Krashes (NIDDK)
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: Forward and reverse genetic screening of macrophages and epithelial cells to identify host factors controlling nontuberculous mycobacterial infection

UK Mentor: Dr. Jasmine Fisher
University: CambridgeDepartment of Biochemistry
NIH Mentor:
Project: Invent and implement new radioactive probes for imaging specific molecular targets in animal and human brain with positron emission tomography

UK Mentor: Prof. Rebecca Fitzgerald
University: CambridgeMRC Cancer Unit
NIH Mentor: Dr. Christian Abnet (NCI/DCEG)
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: 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: 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: 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: 

UK Mentor: Prof. Rita Horvath
University: Cambridge, Department of Clinical Neurosciences
NIH Mentor: Dr. Carsten Bӧnnemann (NINDS)
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: 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: Transcriptional and post-transcriptional dysregulation in ALS

UK Mentor: Prof. Matthias Landgraf
University: Cambridge, Department of Zoology
NIH Mentor: Dr. Mihaela Serpe (NICHD)
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: 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:
Project:

UK Mentor: Prof. Stefan Marciniak
University: Cambridge, Cambridge Institute for Medical Research
NIH Mentor: Dr. Craig Blackstone (NINDS)
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. Keith Martin
University: Cambridge, Department of Clinical Neurosciences (Ophthalmology)
NIH Mentor: Dr. Herb Geller (NHLBI)
Project: The project will develop new methods to stimulate axon regeneration from the retina to the brain. The first method will be based on expressing integrins and integrin activators in ganglion cells, which has been dramatically successful in the spinal cord. The second method will be to activate signalling via phosphatidylinositols to stimulate axonal transport and motility. The project will also examine guidance of regenerating axons. Co-supervised by Professors James Fawcett and Keith Martin.

UK Mentor: Prof. Patrick Maxwell
University: Cambridge, Institute for Medical Research
NIH Mentor: 
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: 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: Prof. Yorgo Modis
University: Cambridge, Department of Medicine
NIH Mentor: Dr. Tom Misteli (NCI/CCR)
Project: Molecular mechanism of transgene silencing by the Human Silencing Hub (HUSH) and MORC2

UK Mentor: Prof. Yorgo Modis
University: Cambridge, Department of Medicine
NIH Mentor: 
Project: Double-stranded RNA (dsRNA) is a potent proinflammatory signature of viral infection. Long cytosolic dsRNA is recognized by MDA5. The cooperative assembly of MDA5 into helical filaments on dsRNA nucleates the assembly of a multiprotein type-I-interferon signaling platform. We have shown through a combination of biophysical studies that MDA5 is a flexible multidomain protein that binds dsRNA cooperatively and forms ATP-sensitive filaments on dsRNA. Our work, which includes a low resolution helical image reconstruction from negatively stained EM micrographs (doi/10.1073/pnas.1212186109), has allowed us to propose a mechanism for the activation of MDA5-dependent signaling by dsRNA in which MDA5 filaments provide a helical structural scaffold that recruits the downstream signaling molecule MAVS. This model is compelling given that MAVS aggregates through its caspase recruitment domain (CARD) into prion-like fibrils with potent inflammatory response, however in order to validate this model and understand the signaling mechanism in atomic-level detail high resolution structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis are required.

We have determined a cryoEM structure of the MDA5-dsRNA filament at 3.7 Å resolution (https://doi.org/10.1101/376319). The structure allowed us to identify the filament forming interfaces, which we validated using a cell signaling assay. These contacts are critical in signaling as they encode the positive cooperativity of MDA5-dsRNA binding, which governs MDA5 filament assembly and determines the dsRNA length specificity of MDA5. It is clear from our first round of image reconstruction that the MDA5-dRNA filaments have a variable helical twist. Unexpectedly, the helical twist appears to be correlated with the presence or absence of ATP in the active site. Moreover, structures with different twists have different footprints on dsRNA. This suggests that ATP binding and hydrolysis are coupled with changes in twist and RNA binding footprint. The goal of this MPhil project is to fully elucidate the role of ATP binding and hydrolysis in RNA sensing by MDA5. The experimental approaches will be to determine high-resolution cryoEM structures of the filament in the presence of different concentration of nucleotide analogs, and to perform ATP hydrolysis assays and cell signaling assays with ATPase mutants. This project will answer the key outstanding question of how ATP hydrolysis by MDA5 and related dsRNA sensors contributes to their antiviral activity. MDA5 is an excellent potential target for clinical intervention. 18 mutations in MDA5 have been reported to cause severe human disease, including Aicardi–Goutières and Singleton Merten syndromes. Our identification of the filament forming interfaces has predictive value for clinicians, as mutations affecting the filament forming interfaces of MDA5 can be expected to cause disease. Our structures of MDA5 bound to various ATP analogs provide a platform for the design of small molecule antagonists of MDA5 for potential use to treat autoimmune disorders.

UK Mentor: Dr. Sean Munro
University: Cambridge, MRC Lab of Molecular Biology
NIH Mentor: Dr. Justin Taraska (NHLBI)
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: 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: 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: 

  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: 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:

UK Mentor: Prof. Olivier Restif
University: Cambridge, Department of Veterinary Medicine
NIH Mentor: Dr. Vincent Munster (NIAID)
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: 

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: 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: 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 Spigone
University: Cambridge, Department of Chemistry
NIH Mentor: 
Project: 

UK Mentor: Prof. Colin W Taylor
University: Cambridge, Department of Pharmacology
NIH Mentor: Dr. Tamas Balla (NICHD)
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: Novel approaches to cancer diagnostics in primary care


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This Page Last Updated on November 9, 2018
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