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Prospective Students

 

PROSPECTIVE STUDENTS

 

Collaboration Opportunities

 

Collaboration Opportunities

The NIH Intramural Research Program (IRP) represents a community of approximately 1,200 tenured and tenure-track investigators. NIH investigators in over 17 institutes at the NIH have welcomed NIH Oxford-Cambridge Scholars into their labs.

One of the key elements of the NIH Oxford-Cambridge Scholars Program (OxCam) is collaboration. It is important that our students be able to find mentors at both the NIH and The Universities of Oxford or Cambridge.  This page is dedicated to assisting our students with this process by posting project opportunities from potential mentors. (For tips on choosing a mentor, please visit our Training Plan)

There are often times that an investigator will be working on, or planning, a project and would value the addition of a PhD student to his/her lab.  These investigators could also benefit from the international collaborative opportunities and interdisciplinary techniques that are available by having an NIH OxCam scholar on their team.

This site will assist with many facets of the mentor and project defining process:

  • Potential mentors can advertise for students
  • Students can “shop” for mentors and projects
  • Mentors and students can “shop” for potential collaborators

This page is a perpetual work-in-progress; projects end, budgets change, and positions are filled, but we want this to be a starting point for inspiration and ideas.

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 Mental Health
National Institute of Neurological Disorders and Stroke
Oxford
Cambridge

National Cancer Institute (NCI)

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

NIH mentor: Dr. Genoveffa (Veffa) Franchini (NCI/CCR)
UK mentor:
Prof. Jonathan L Heeney
University:
Cambridge, Department of Veterinary Medicine
Project:
Proposed projects; 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.

NIH mentor: Dr. Amy Berrington de Gonzalez (NCI)
UK mentor: Prof. Jane Green
University: Oxford
Project: Diet and brain tumors in the UK million women study and the US NIH-AARP diet and health study.

NIH mentor: Dr. Eric Freed (NCI)
UK mentor: Prof. Andrew Lever; Prof. 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

The transcription of retroviral genes newly integrated into the human genome is repressed by the Human Silencing Hub (HUSH). The HUSH complex represses the expression of newly integrated genes by recruiting SETDB1 and MORC2 to the site of integration. SETDB1 deposits the repressive epigenetic mark H3K9me3. MORC2 is GHKL-family ATPase. Mutations in MORC2 can cause severe neuropathies to as seen in Charcot Marie Tooth (CMT) disease and spinal muscular atrophy (SMA). To address how HUSH identifies target genes for silencing and how MORC2 contributes to transcriptional repression, we are examining the molecular structures and biochemical properties of MORC2 and the HUSH constituent proteins, TASOR, MPP8 and periphilin. We have found that MORC2 forms dimers in an ATP-dependent manner. A crystal structure of MORC2 reveals an ATPase fold similar to that of Hsp90. A coiled-coil insertion unique to MORC1/2 appears to form an ATP-dependent clamp around genomic DNA. Disease-causing mutations map to the MORC2 ATPase domain. Mutations associated with CMT and SMA cause a decrease or increase of MORC2 ATPase activity, respectively. Disease mutations alter the dimerization dynamics of MORC2 through multiple and distinct structural mechanisms. Based on this work we have developed the hypothesis that MORC2 disease mutations inhibit the chromatin remodeling activity of MORC2 by destabilizing the ATP-dependent dimerization of MORC2. We propose this to be the molecular basis of MORC2-related neuropathies. Our work raises many questions, which must be answered in order for us to fully understand the biological function of MORC2. The aim of this PhD project is to address the following specific open questions: (1) What is the function of the C-terminal half of MORC2 (residues 604-1032)? (2) How does MORC2 bind chromatin, and does it recognize any common epigenetic marks on histone tails? (3) What are the nature and mechanism of MORC2 chromatin remodeling? We will answer these questions by applying a complementary set of biochemical and structural approaches including electron cryomicroscopy (cryoEM). Ultimately, our work may contribute to the development of MORC2 inhibitors or agonists that could be useful as a novel treatment for various motor and sensory neuropathies including CMT and SMA.

References
1. Tchasovnikarova et al (2015) Science 348:1481-1485.
2. Tchasovnikarova et al (2017) Nat Genet 49:1035–1044

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.

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: 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

National Heart, Lung, and Blood Institute (NHLBI)

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: IFNγ-producing T helper 1 (Th1) cells are required for defence against some infections but may also contribute to the pathogenesis of autoimmune disease. Autocrine complement activation has recently emerged as key controller of human Th1 immunity; Activation of the complement regulator CD46 and the C3aR expressed by CD4+ T cells via autocrine generated ligands C3b and C3a, respectively, are critical to IFNγ production.
Systemic lupus erythematosus (SLE) is an antibody-mediated autoimmune disease. We have shown that CD46-regulated Th1 contraction in SLE is impaired due to increased matrix metalloprotease (MMP)-9-mediated shedding of soluble CD46 on Th1 cells (Kemper Lab).
Dendritic cells (DC) are important antigen presenting cells and express a variety of receptors, including IgG antibody receptors (FcyRs). We have shown that FcyR cross-linking on DC results in MMP-9 secretion (Clatworthy Lab). Together, these data raise the question of whether DC could impact autocrine complement activation by 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.

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. Ken Olivier (NHLBI) & Dr. Steve Holland (NIAID)
UK Mentor: Prof. Andres Floto
University: Cambridge, Department of Medicine
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.

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.

NIH mentor: Dr. Antonina Roll-Mecak (NHLBI / NINDS)
UK mentor:
University:
Project: Mechanistic dissection of tubulin posttranslational modifications in health and disease.

National Human Genome Research Institute (NHGRI)

NIH mentor: Dr. Philip Shaw (NHGRI)
UK mentor: Collaborators at both universities
University:
Project: Interplay between genes 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. 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:Cambridge, Department of Medicine
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.

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.

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. Susan Pierce (NIAID)
UK Mentor: Prof. Patrick Maxwell
University: Cambridge, Institute for Medical Research
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.

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: Prof. Eamonn Maher
University: Cambridge, Department of Medical Genetics
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. 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. 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. 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. Jeffrey Kopp (NIDDK)
UK mentor:
University:
Project: Studying the function of APOL1 genetic variants using transgenic mice and cell culture models.

 

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 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. Bibi Bielekova (NINDS)
UK mentor:
University:
Project: Development of cell-specific or process-specific biomarkers for CNS diseases.

NIH mentor: Dr. Avindra Nath (NINDS)
UK mentor:
University:
Project: Determining the role of endogenous retroviruses in the pathophysiology of neurological diseases.

NIH mentor: Dr. Daniel Reich (NINDS)
UK mentor:
Prof. Robin Franklin
University:
Cambridge
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:
University:
Project: Mechanistic dissection of tubulin posttranslational modifications 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

Oxford

NIH mentor: Dr. Amy Berrington de Gonzalez (NCI)
UK mentor: Prof. Jane Green
University: Oxford
Project: Diet and brain tumors in the UK million women study and the US NIH-AARP diet and health study.

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

Cambridge

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

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: Multiple potential NIH collaborators
UK Mentor: Dr. Gonçalo Bernardes
University: Cambridge, Department of Chemistry
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.

NIH Mentor: Multiple potential NIH collaborators
UK Mentor: Prof. Guy Brown
University: Cambridge, Department of Biochemistry
Project: Targeting microglial phagocytosis of synapses and neurons in neurological diseases and aging. Microglia are brain macrophages that protect the brain by phagocytosing pathogens, debris, protein aggregates and excess synapses. So promoting this phagocytosis may be protective in some conditions. However, during brain inflammation, excessive microglial phagocytosis of synapses and neurons, may be detrimental, so blocking particular phagocytic receptors and opsonins may beneficial in aging, stroke, trauma, Parkinson's disease and Alzheimer's disease. We will look at which interventions in models of aging and neurological disease.

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: Multiple potential NIH collaborators
UK mentor:
Dr. Patrick Chinnery
University:
Cambridge, Department of Clinical Neurosciences
Project:

1. Determine the role of mitochondria in immune cell function in health and disease

2. Determine the role of somatic mutations in neurodegenerative diseases

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: IFNγ-producing T helper 1 (Th1) cells are required for defence against some infections but may also contribute to the pathogenesis of autoimmune disease. Autocrine complement activation has recently emerged as key controller of human Th1 immunity; Activation of the complement regulator CD46 and the C3aR expressed by CD4+ T cells via autocrine generated ligands C3b and C3a, respectively, are critical to IFNγ production.
Systemic lupus erythematosus (SLE) is an antibody-mediated autoimmune disease. We have shown that CD46-regulated Th1 contraction in SLE is impaired due to increased matrix metalloprotease (MMP)-9-mediated shedding of soluble CD46 on Th1 cells (Kemper Lab).
Dendritic cells (DC) are important antigen presenting cells and express a variety of receptors, including IgG antibody receptors (FcyRs). We have shown that FcyR cross-linking on DC results in MMP-9 secretion (Clatworthy Lab). Together, these data raise the question of whether DC could impact autocrine complement activation by 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.

NIH mentor: Multiple potential NIH collaborators
UK mentor:
Dr. Jasmin Fisher
University:
Cambridge, Department of Biochemistry
Project:
In silico mechanistic models to identify novel cancer therapies.

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

NIH Mentor: Dr. Steve Holland (NIAID) & Dr. Ken Olivier (NHLBI)
UK Mentor: Prof. Andres Floto
University:
Cambridge, Department of Medicine
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.

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.

NIH mentor: Dr. Daniel Reich (NINDS)
UK mentor:
Prof. Robin Franklin
University:
Cambridge
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. Genoveffa (Veffa) Franchini (NCI/CCR)
UK mentor:
Prof. Jonathan L Heeney
University:
Cambridge, Department of Veterinary Medicine
Project:
Proposed projects; 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.

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. Karel Pacak (NICHD)
UK Mentor: Prof. Eamonn Maher
University: Cambridge, Department of Medical Genetics
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. 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. Susan Pierce (NIAID)
UK Mentor: Prof. Patrick Maxwell
University: Cambridge, Institute for Medical Research
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.

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

The transcription of retroviral genes newly integrated into the human genome is repressed by the Human Silencing Hub (HUSH). The HUSH complex represses the expression of newly integrated genes by recruiting SETDB1 and MORC2 to the site of integration. SETDB1 deposits the repressive epigenetic mark H3K9me3. MORC2 is GHKL-family ATPase. Mutations in MORC2 can cause severe neuropathies to as seen in Charcot Marie Tooth (CMT) disease and spinal muscular atrophy (SMA). To address how HUSH identifies target genes for silencing and how MORC2 contributes to transcriptional repression, we are examining the molecular structures and biochemical properties of MORC2 and the HUSH constituent proteins, TASOR, MPP8 and periphilin. We have found that MORC2 forms dimers in an ATP-dependent manner. A crystal structure of MORC2 reveals an ATPase fold similar to that of Hsp90. A coiled-coil insertion unique to MORC1/2 appears to form an ATP-dependent clamp around genomic DNA. Disease-causing mutations map to the MORC2 ATPase domain. Mutations associated with CMT and SMA cause a decrease or increase of MORC2 ATPase activity, respectively. Disease mutations alter the dimerization dynamics of MORC2 through multiple and distinct structural mechanisms. Based on this work we have developed the hypothesis that MORC2 disease mutations inhibit the chromatin remodeling activity of MORC2 by destabilizing the ATP-dependent dimerization of MORC2. We propose this to be the molecular basis of MORC2-related neuropathies. Our work raises many questions, which must be answered in order for us to fully understand the biological function of MORC2. The aim of this PhD project is to address the following specific open questions: (1) What is the function of the C-terminal half of MORC2 (residues 604-1032)? (2) How does MORC2 bind chromatin, and does it recognize any common epigenetic marks on histone tails? (3) What are the nature and mechanism of MORC2 chromatin remodeling? We will answer these questions by applying a complementary set of biochemical and structural approaches including electron cryomicroscopy (cryoEM). Ultimately, our work may contribute to the development of MORC2 inhibitors or agonists that could be useful as a novel treatment for various motor and sensory neuropathies including CMT and SMA.

References
1. Tchasovnikarova et al (2015) Science 348:1481-1485.
2. Tchasovnikarova et al (2017) Nat Genet 49:1035–1044

NIH Mentor: Multiple potential NIH collaborators
UK Mentor: Dr. Timothy O'Leary
University: Cambridge, Department of Engineering
Project: Models of ion channel regulation in single cells and small circuits; Modelling robust neuromodulation; Regulation and control of neural activity and circuit dynamics

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

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

 


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This Page Last Reviewed on September 19, 2017