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Research Opportunities

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Prospective Students

The goal of the NIH Oxford-Cambridge (OxCam) Scholars Program is to create, foster, and advance unique and collaborative research opportunities between NIH laboratories and laboratories at the University of Oxford or the University of Cambridge. Each OxCam Scholar develops a collaborative research project that will constitute his/her doctoral training. Each Scholar also select two mentors – one at the NIH and one in the UK – who work together to guide the Scholar throughout the research endeavor.

Students may select from two categories of projects: Self-designed or Prearranged. OxCam Scholars may create a self-designed project, which enables students to develop a collaborative project tailored to his/her specific scientific interests by selecting one NIH mentor and one UK mentor with expertise in the desired research area(s). Alternatively, students may select a prearranged project provided by NIH and/or UK Investigator(s) willing to mentor an OxCam Scholar in their lab.

Self-designed Projects: Students may create a novel (or de novo) project based on their unique 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. Students may visit https://irp.nih.gov to identify NIH PIs performing research in the area of interest. For additional tips on choosing a mentor, please visit our Training Plan.

Prearranged Projects: Investigators at NIH or at Oxford or Cambridge have voluntarily offered collaborative project ideas for NIH OxCam Scholars. These projects are provided below and categorized by research area, NIH Institute/Center, and University. In some cases, a full collaboration with two mentors is already in place. In other instances, only one PI is identified, which allows the student to select a second mentor to complete the collaboration. Please note that prearranged project offerings are continuously updated throughout the year and are subject to change.

22 Search Results

461
Category:
Immunology
Project:

Investigating the impact of regulatory cell therapy on local immune response in kidney allografts

Project Listed Date:
Institute or Center:
N/A
NIH Mentor:

Dr. Joanna Hester

UK Mentor:
N/A
University:
Oxford
Project Details:

Regulatory T cells (Tregs) have the ability to suppress allogeneic immune responses and have therefore become interesting as a possible cellular therapy.  Our group is leading a phase II randomised clinical trial utilising Tregs as a cellular therapy for kidney transplant recipients.

The proposed project aims to in depth investigate the local immune response within the transplanted allograft, specifically focusing on infiltrating regulatory T cells and their local interactions with other infiltrating immune cells, utilising renal biopsy samples from the cell therapy trial.  We hypothesise, that cellular therapy with regulatory T cells will result in trafficking of the Tregs cells to the allograft and creation of a local tolerogenic microenvironment.

We are proposing to utilise our unique collection of Treg treated patients’ biopsy samples employing the cutting-edge technology of spatial transcriptomics and single cell RNA sequencing to determine the cellular and molecular composition of leukocyte infiltrates in allograft biopsies, dissect cellular interactions in situ and determine Treg homing to the allograft.

456
Category:
Immunology
Project:

Examining the anatomical and molecular aspects of new gene involvement and the effects of antigen-specific therapy

Project Listed Date:
Institute or Center:
National Institute of Allergy and Infectious Diseases (NIAID)
NIH Mentor:

Dr. Michael Lenardo 

University:
Oxford
Project Details:

Autoimmune central nervous system (CNS) demyelinating diseases, especially multiple sclerosis (MS) are a major public health burden and poorly controlled by current immunosuppressants. More precise immunotherapies with higher efficacy and fewer side effects are sought.

We are investigating genetic basis of autoimmunity genomic DNA sequencing of the largest cohort of MS patients and family members (14,000 specimens) in an effort to improve therapy. We are also evaluating the effectiveness and mechanism of an
injectable myelin-based antigenic polyprotein MMPt to achieve antigen-specific treatment of MS. We find that it suppresses mouse experimental autoimmune encephalomyelitis (EAE) without major side effects. MMPt induces rapid apoptosis of the encephalitogenic T cells and suppresses inflammation in the affected CNS. Intravital microscopy shows that MMPt is taken up by perivascular F4/80+ cells but not conventional antigen-presenting dendritic cells, B cells, or microglia. MMPt-stimulated F4/80+ cells induce reactive T-cell immobilization and apoptosis in situ, resulting in reduced infiltration of inflammatory cells and chemokine production.

Our study will examine the anatomical and molecular aspects of new gene involvement and the effects of antigen-specific therapy to reveal new mechanisms that explain how cognate antigen suppresses CNS inflammation and may be applicable for effectively and safely treating demyelinating diseases.

454
Category:
Immunology
Project:

Immuno-parasitology and epidemiology of helminths and SARS-CoV-2 coinfections

Project Listed Date:
Institute or Center:
National Institute of Allergy and Infectious Diseases (NIAID)
NIH Mentor:

Dr. P'ng Loke 

University:
Oxford
Project Details:

There is a poor understanding of the effects of co-infection with parasitic helminths on SARS-CoV-2 infection. National Institute of Allergy and Infectious Disease (NIAID) and University of Oxford researchers are collaborating to study the effects of helminth co-infection on the immunological and patient-centered clinical outcomes of SARS-CoV-2 infection in India. In addition to deep immunological and microbiome profiling, they will investigate relevant comorbidities and socioecological confounders, as well conduct detailed epidemiological analyses of (co)infection risk factors, clinical/medical care outcomes. The project intends to discern whether SARS-CoV-2 infection is more or less likely among individuals with helminth infections when compared to individuals without helminth coinfections and to determine whether SARS-CoV-2 coinfection with helminths can cause antagonistic or synergistic long-lasting clinical outcomes, as well as detailed immune-phenotypes of infected individuals. Field studies will be conducted in the Tiruvallur District of Tamil Nadu, India by a NIAID-Indian Council on Medical Research (ICMR) International Center for Excellence in Research team based in Chennai.

This project is an exciting opportunity to combine work in immunology with epidemiology. You will join multidisciplinary labs at the NIH and Oxford

449
Category:
Immunology
Project:

Investigating B and T cell populations in health and disease

Project Listed Date:
Institute or Center:
N/A
NIH Mentor:
N/A
University:
Oxford
Project Details:

How are different B cell populations developmentally linked in human health and disease?

We are investigating the generation, function and plasticity of B cell populations in human health. In particular, we are interested in how different lymphocyte subsets are developmentally linked and differences in function, and therefore providing a platform to understand how B cell fate may be different in human disease. We are defining how B cells select a particular developmental pathway, and will use this information to develop methods for modulating B cell function as potential therapeutic approaches.

How can B and T cells may be therapeutically modulated across cancers and autoimmune diseases?

There is accumulating evidence for the role of both T and B cells in modulating immune responses to both solid tumours and haematological malignancies. We are investigating the contributions, function and heterogeneity of B and T cells on the immune responses to tumours and their potential role in cancer detection and treatment. We are determining the nature of B and T cell immuno-surveillance, regulation and activation across cancers and autoimmune diseases, as well as the immunological features associated with better prognosis and immunomodulation. With this, we aim to highlight novel therapeutic avenues. Our lab is affiliated with the Oxford Cancer Centre (https://www.cancer.ox.ac.uk/research/research-themes/developments-in-immuno-oncology) and non-cancer clinicians, with strong clinical links to a wide range of hard-to-treat diseases.

What is the effect of genetic and environmental variation on B and T cell fate?

Immunological health relies on a balance between the ability to mount an immune response against potential pathogens and tolerance to self. B and T cells are key to the immune response by producing antibodies and cytotoxic T cells. B/T cell clones selectively expand following antigen recognition by B and T cell receptors (BCR and TCR) respectively. BCRs are the membrane-form of antibodies and are generated through DNA recombination resulting in the potential to recognise a vast array of pathogens. Defects in the ability to mount effective B cell or T cell responses have been implicated in infectious susceptibility, impaired surveillance of cancer and immunodeficiencies, whereas a breakdown of immunological tolerance has been attributed to autoimmune diseases such as through autoantibody production and reduced numbers of regulatory B/T cells. Through integrating genomics, bulk and single-cell transcriptomics, and metabolomics data, serological, B /T cell repertoire and viromics datasets we will investigate the effect of both genetic variation and environmental factors on B cell fate, regulation, and the relationship to disease susceptibility.

448
Category:
Immunology
Project:

Defining the role of shared T-cell receptor clonotypes in SARS-CoV-2 infection

Project Listed Date:
Institute or Center:
N/A
NIH Mentor:
N/A
UK Mentor:

Prof. Peijun Zhang

University:
Oxford
Project Details:

T cells are a major component of adaptive immune response, continuously screening lymphoid tissues for antigen peptides presented by major histocompatibility complex (peptide/MHC or pMHC)3. These antigen peptides are recognized by T-cell receptors (TCRs). Thymocytes with a low-affinity TCRs mature into T cells and enter the lymphoid organs, where they are exposed to foreign antigen peptides by MHC molecules from antigen-presenting cells including macrophages, dendritic cells, and B-cells, during infection. When the T-cell receptors bind to antigenic peptide, T-cells are activated and undergo clonal expansion, resulting in immune response. CD8+ T cells play an important for immune response and viral clearing, but their role in protection and pathogenesis of SARS-CoV-2 remains poorly understood4. In addition to extensively studied spike protein, open reading frame 3a (ORF3a), a highly conserved protein within the Betacoronavirus subgenus, has been considered as a potential target for vaccines or therapeutics, with deletion of ORF3a resulting in decreased viral titer and morbidity. We have identified shared CD8+ T cell clonotypes responding to a ORF3a in COVID-19 infections.  Importantly, shared clonotypes in severe COVID-19 infections provides a target for development of novel antiviral immunotherapies. The aim of this project is to analyse shared TCR clonotypes in ORF3a recognition and provide structural basis for the recognition of ORF3a-pMHC complex by T-cell receptors.

429
Category:
Immunology
Project:

Understanding immunological processes that drive damage during neuroinflammation

Project Listed Date:
Institute or Center:
N/A
NIH Mentor:
N/A
UK Mentor:

Prof. Adrian Liston

University:
Cambridge
Project Details:

The brain is a site of relative immune privilege, long considered isolated from the peripheral immune system. We recently identified a population of resident T cells in the healthy mouse and human brain, important for the maturation of microglia (Pasciuto et al, Cell 2020). By analysing the kinetics of migration between the blood and brain, we found that the key bottleneck controlling the number of anti-inflammatory regulatory T cells in the brain was the high rate of cell death the cells exhibit when housed within the brain. Through developing a unique tool, with potential therapeutic application, we were able to deliver a biologic directly to the brain and enhance the size of the regulatory T cell population. The approach protects mice from brain damage following traumatic brain injury, stroke and multiple sclerosis. In this project we wish to explore the immunological processes that drive damage during neuroinflammation, and to harness immune-modulating biologics to prevent damage to the brain. 

418
Category:
Immunology
Project:

Elucidating the role of innate-like B lymphocytes in defense and homeostasis of host mucosal surfaces

Project Listed Date:
Institute or Center:
National Institute of Allergy and Infectious Diseases (NIAID)
NIH Mentor:

Dr. Stefan Muljo

UK Mentor:

Prof. Martin Turner

University:
Cambridge
Project Details:

Immunity and immune-tolerance at mucosal and other barrier surfaces is vital for host survival and homeostasis with antibodies or immunoglobulins (Ig) playing a key role. However, the specific roles of B cell sub-types, particularly, the innate-like B-1 cell subset is poorly understood. The surgeon James Rutherford Morrison (1906) called the omentum in the peritoneal cavity the "abdominal policeman" and it promotes gut IgA production by peritoneal B-1 cells. IgA is the most abundantly produced antibody isotype and is known to be important for mucosal immunity. It is estimated that ~50% of IgA is derived from B-1 cells. In addition, B-1 cells are thought to be important because they make T cell-independent “natural” IgM circulating in our blood, and they can rapidly respond to mucosal perturbations such as an infection. By contrast, it will take conventional B-2 cells weeks to mount a germinal center (GC) reaction and generate antibodies that have undergone T cell-dependent affinity maturation and isotype switching. Textbooks currently do not entertain the possibility that B-1 cells can also participate in GC reactions. This project aims to challenge such an assumption. After all, B-1 cells in the gut mucosa and probably other mucosal tissues can undergo class switch recombination to IgA. However, the differentiation program that leads to this distinct pathway of IgA production is not well understood: for example, it is unknown if this process occurs outside or within GCs in mucosa-associated lymphoid tissues (MALT). Expertise on B-1 cells in the Muljo lab and the GC reaction in the Turner lab will be combined to explore this potentially paradigm-shifting research. Both wet-bench and bioinformatic research opportunities are available.

Students will learn about the fundamentals of transcriptional; epigenetic and post-transcriptional regulation; immunometabolism; in vivo CRISPR screening; CRISPR editing in primary B cells; and systems immunology. The combination of classical immunological techniques and cutting-edge, multi-disciplinary approaches will enable important discoveries to define the in vivo biology of B-1 cells. Ultimately, we seek novel insights that can be translated to inform vaccine design targeted to activate B-1 cells and/or therapeutics to inhibit their activity when necessary.

 

Recent publications:

Turner, D. J., Saveliev, A., Salerno, F., Matheson, L. S., Screen, M., Lawson, H., Wotherspoon, D., Kranc, K. R., and Turner, M. (2022). A functional screen of RNA binding proteins identifies genes that promote or limit the accumulation of CD138+ plasma cells. eLife, 11, e72313. PMID: 35451955; DOI: 10.7554/eLife.72313.

Osma-Garcia, I.C., Capitan-Sobrino, D., Mouysset, M., Bell, S.E., Lebeurrier, M., Turner, M. and Diaz-Muñoz, M.D. (2021). The RNA-binding protein HuR is required for maintenance of the germinal centre response. Nature Communications, 12(1):6556. PMID: 34772950; DOI: 10.1038/s41467-021-26908-2.

Wang, S., Chim, B., Su, Y., Khil, P., Wong, M., Wang, X., Foroushani, A., Smith, P. T., Liu, X., Li, R., Ganesan, S., Kanellopoulou, C., Hafner, M. and S. A. Muljo. (2109). Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3. Genes & Development, 33: 1048-1068. PMID: 31221665; DOI: 10.1101/gad.325100.119.

351
Category:
Immunology
Project:

CRISPR screens for Tfh cell development and function in response to vaccination and infection

Project Listed Date:
Institute or Center:
National Institute of Allergy and Infectious Diseases (NIAID)
University:
Cambridge
Project Details:

T follicular helper (Tfh) cells provide critical signals to B cells for the formation of germinal centers, which are essential for the generation of long-lasting, affinity matured antibody responses and long-lived B cell memory. Thus, Tfh cells are crucial for successful responses to vaccines. While many efforts have focused on identifying regulators of Tfh cell formation and function, we still only have a partial understanding of the signals shaping the Tfh cell fate, as suggested by the fact that we can only partially recapitulate the differentiation of Tfh cells in vitro.  Using CRISPR-Cas9-mediated gene editing screens in primary mouse T cells, combined with adoptive T cell transfers, we aim to uncover novel factors and pathways playing fundamental roles in the differentiation and function of Tfh cells during viral infection and vaccination. Knowledge gained from this work could have important implications for the therapeutic regulation of these cells during both infection and vaccination.

349
Category:
Immunology
Project:

CRISPR-mediated screens for Phosphoinositide signaling in T cell

Project Listed Date:
Institute or Center:
National Institute of Allergy and Infectious Diseases (NIAID)
University:
Cambridge
Project Details:

The Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that control diverse signalling pathways affecting gene-transcription, cellular adhesion and trafficking, autophagy and metabolism via the generation of PIP3. While some of these readouts are controlled by the evolutionarily conserved PI3K-AKT-FOXO, PI3K-AKT-mTOR axes, there is a diverse network of PI3K effectors that are less well studied, especially in lymphocytes, but which nonetheless can have profound effects on lymphocyte biology. We have recently used CRISPR/Cas9 to perform a targeted screen of PI3K effectors by generating a library that specifically targets PIP3-binding proteins. Screening for genes that affect T cell adhesion, we identified RASA3 as a key protein linking PI3K to the activation of the integrin LFA-1 and found that RASA3 is critical for T cell migration, homeostasis and responses to immunization. We have now generated extended CRISPR/Cas9 libraries that target the entire PI3K-ome (including the kinases, phosphatases and all known effector proteins). Potential projects include designing and implementing new screens for downstream readouts of PI function, including autophagy, endocytosis, regulation of humoral immunity in vivo or other readouts, and/or understanding how RASA3 regulates T cell function and the signaling pathways involving this key regulator of immune cell migration.

237
Category:
Immunology
Project:

Understanding immune correlates of protective immunity

Project Listed Date:
Institute or Center:
National Cancer Institute (NCI)
UK Mentor:
N/A
University:
N/A
Project Details:

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 immunodeficiencies.


The first 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 immunodeficiencies leads to chronic immune activation and poor prognosis, with an emphasis on mucosal immunity.

236
Category:
Immunology
Project:

Examining germinal centre (GC) biology during normal function and in aging

Project Listed Date:
Institute or Center:
National Human Genome Research Institute (NHGRI)
University:
Cambridge
Project Details:

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

234
Category:
Immunology
Project:
N/A
Project Listed Date:
Institute or Center:
National Institute of Allergy and Infectious Diseases (NIAID)
NIH Mentor:

Dr. Michael Lenardo

UK Mentor:

Prof. Ken Smith

University:
Cambridge
Project Details:

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.

226
Category:
Immunology
Project:

Investigating the impact of dendritic cell-T cell interactions on autocrine complement activation in CD4 T cells

Project Listed Date:
Institute or Center:
National Heart, Lung, and Blood Institute (NHLBI)
NIH Mentor:

Dr. Claudia Kemper

University:
Cambridge
Project Details:

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.

220
Category:
Immunology
Project:

Examining inflammasome formation using microscopy

Project Listed Date:
Institute or Center:
National Institute of Allergy and Infectious Diseases (NIAID)
UK Mentor:
N/A
University:
N/A
Project Details:

The inflammasome consists of a cytosolic NOD-like receptor, an adaptor molecule (ASC) and an effector molecules caspase 1.  Once activated the inflammasome processes inflammatory cytokines such as interleukin 1 beta (IL1B) and IL18 as well as driving an aggressive form of cell death (pyroptosis).  Inflammasomme protein complexes are central to sustaining inflammation in acute diseases (like COVID-19 associated ARDS) or chronic conditions (such as Alzheimer’s Disease, Parkinson’s, diabetes, arthritis).  Patients with rare autoactivating mutations in the NLR proteins have basally active inflammasomes leading to severe autoinflammatory syndromes. How inflammasome complexes form within the cell, particularly in patients with autoactivating mutations in NLRs are poorly understood.  

The aims of this project are as follows:
1.      Identify the molecular mechanisms by which the gain of function mutations causes constitutive activation of the NLRs
2.      Determine why gain of function mutations in different NLRs (NLRP3 and NLRC4) result in differences in inflammasome cytokine production with NLRP3 biased towards IL1B and NLRC4 towards IL18
3.      Visualise how gain of function mutations alter inflammasome formation by visualising the protein complexes at super resolution and atomic resolution

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

204
Category:
Immunology
Project:

Are metabolites generated by the microbiota key to a young immune system?

Project Listed Date:
Institute or Center:
N/A
NIH Mentor:
N/A
UK Mentor:

Prof. Katja Simon

University:
Oxford
Project Details:
N/A
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