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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.

164 Search Results

395
Category:
Stem Cell Biology
Project:

Elucidating the role of disease modifying gene variants in inherited cardiomyopathies using induced pluripotent stem cell derived cardiomyocytes and CRISPR/Cas-9

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

Our group is interested in uncovering and understanding key mechanisms of disease that affect cardiac muscle function. We have a particular interest in understanding how regulation of cardiac muscle contraction is altered in common acquired and inherited cardiovascular diseases. We do this by using cutting edge techniques in cellular imaging, employing human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), and CRISPR/Cas-9 to understand human cardiovascular disease in the dish.
 

We have two key focuses in the lab:

  1. Understanding how inherited heart conditions including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) alter cardiomyocyte function. We do this by using CRISPR Cas-9 genome engineering in combination with iPSC-CMs to screen how HCM and DCM causing variants cause disease. We can then use these systems to screen novel therapeutics in the dish. We have designed multiple techniques to make these analyses feasible and rapidly deployable: SarcTrack and CalTrack.
     
  2.  Investigate the processes that alter cardiac muscle function in acquired cardiac diseases including myocardial infarction, atrial fibrillation, and heart failure. We are able to use biochemical techniques twinned with fluorescent imaging to assess how cardiac myosin states are altered in disease tissues. This technology allows us to uncover key disease mechanisms that alter heart muscle function, allowing insight into these common heart muscle diseases. 
     

We have multiple key collaborations within the University of Oxford and internationally. Together we focus on pushing the boundaries of understanding in acquired and inherited cardiovascular disorders of the heart muscle. Within the group we have an inclusive and diverse set of researchers who have a wide range of cutting-edge expertise. Within the wider lab environment and our collaboration network we have over 20 researchers in this area.
 

Scientific training opportunities in the lab include but are not limited to:
 

  1. Induced pluripotent stem cell culture
  2. Techniques for iPSC to cardiomyocyte differentiation
  3. CRISPR/Cas-9 genome engineering
  4. PCR and genetic sequencing
  5. A wide range of standard fluorescent microscopy and confocal microscopy
  6. Phenotyping of cardiomyocyte function with fluorescent probes and genetically encoded protein tags
  7. RNA sequencing and qPCR
  8. Western blotting and phosphoprotein blotting techniques
  9. Drug screening using live cell microscopy

Transferrable skills include but are not limited to:
 

  1. Learning to interact with MatLab and other computing packages for automating and simplifying data analysis.
  2. Using genome viewers and associated software for designing and executing CRISPR/Cas-9 engineering.

References:

  1.  Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin Science Translational Medicine 2019
  2. Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy Circulation 2020
  3. SarcTrack An Adaptable Software Tool for Efficient Large-Scale Analysis of Sarcomere Function in hiPSC-Cardiomyocytes Circulation Research 2019
  4. CalTrack: High-Throughput Automated Calcium Transient Analysis in Cardiomyocytes Circulation Research 2021
  5. Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity Nature Genetics 2021
354
Category:
Virology
Project:

Role of replication and translation complexes (RTCs) in the pathogenesis of retroviruses, flaviviruses and coronaviruses

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

Dr. Peijun Zhang

University:
Oxford
Project Details:

Retroviruses, flaviviruses and coronaviruses are important pathogens capable of causing serious human disease. To replicate and disseminate infection, these viruses hijack host cell machinery, including organelles such as the endoplasmic reticulum, the Golgi apparatus, lipid droplets and the nucleus to generate progeny virions. Sensors within the innate immune system detect virus-induced membrane reorganization, identify virus weak spots, and influence disease progression in this complex virus-host interplay. This project focuses on the innate immune response that specifically targets virus replication and translation complexes (RTCs) anchored at the membrane of cell host organelles. RTCs isolated from these sites will be studied using molecular and cell biology, in combination with bioinformatics, structural biology and high resolution imaging to design novel antiviral interventions.

353
Category:
Cancer Biology
Project:

Metabolic regulation of gene expression in the context of cancer

Project Listed Date:
Institute or Center:
National Cancer Institute (NCI)
NIH Mentor:

Dr. Len Neckers

University:
Cambridge
Project Details:

Emerging evidence suggests an exciting link between metabolism, chromatin and transcription. Metabolism can regulate post-translational modifications of histones which in turn regulate transcription of target genes. Highly proliferative cancer cells re-wire their metabolism to fuel growth, and in turn modify histones to alter gene expression. Identifying mechanisms by which cancer cells re-wire their metabolism and gene expression will identify key vulnerabilities to target using small molecule therapeutics.

Our recent work at NIH has demonstrated links between histone lactylation, gene expression and cancer metabolism (histone lactylation depends on elevated cellular lactate, the end product of glycolysis – a preferred metabolic pathway in cancer). Work in Cambridge has further linked the molecular chaperone HSP90 with gene expression and metabolism in the context of cancer. Harnessing the complementary strengths in the two labs at NIH and Cambridge, the collaborative work will delineate molecular pathways linking small-molecule therapeutics targeting the chaperone HSP90 with cancer metabolism and with specific small-molecule inhibitors of glycolysis. The data we obtain delineating the metabolic dependence of gene expression in cancer will uncover novel and exciting treatment strategies to treat cancers’ metabolic vulnerabilities.

352
Category:
Microbiology and Infectious Disease
Project:

Investigating the impact of Trichuris trichiura infection during Inflammatory Bowel Disease (IBD) using organoids

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

Dr. P'ng Loke

University:
Cambridge
Project Details:

Whipworms (Trichuris trichiura) are intestinal parasites that infect hundreds of millions of people worldwide and cause trichuriasis, a major Neglected Tropical Disease. Whipworms live preferentially in the caecum of their hosts and have a unique life cycle strategy where they establish a multi-intracellular niche within the intestinal epithelia (IE). In this niche, whipworms can remain for years causing chronic infections by modulating intestinal inflammation. During IBD the IE is damaged and recent findings identified a pivotal role of the IE in the maintenance of inflammation. IBD is rare in countries where trichuriasis is endemic, suggesting that the control of inflammation evolved by whipworms in order to persist in their epithelial niche during chronic infections may have beneficial effects for its host by limiting bystander inflammatory pathologies. Current IBD therapies using live parasitic worms, including whipworms (T. trichiura and T. suis), worm secretions and worm-derived synthetic molecules are being trialled to treat IBD.  However, the effects of whipworms on the IE during IBD are poorly understood. Intestinal organoids are in vitro multicellular clusters resulting from stem cell self-renewal and organization that closely recapitulate the composition and architecture of the IE. We have shown that murine caecal organoids (caecaloids) stimulated with extracellular vesicles purified from adult T. muris (mouse whipworm) excretory-secretory (ES) products show a downregulation of genes normally involved in virus responses, specifically type-1 interferon signalling. This data led us to hypothesise that the anti-inflammatory effects of whipworm infections as IBD therapy are partly mediated by direct effects on the IE.

For this PhD project, we will adapt our murine caecal organoid-whipworm model
 to human organoids and T. trichiura. We will generate intestinal organoids from biopsies of IBD patients, healthy controls and individuals experimentally infected with T. trichiura in human challenge infections. These studies will offer insights on the inflammatory and stem cell remodelling pathways modulated by whipworms in the IE and will lead to the dissection of the molecular mechanisms promoting whipworm persistence in the host but also with beneficial effects for therapies on IBD.

 

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.

350
Category:
Neuroscience
Project:

Memory formation during sleep

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

The laboratory investigates the interactions between episodic memory formation and brain dynamics during sleep. How are memories strengthened (‘consolidated’) overnight? What is the role of specific brain rhythms during sleep? Can we use sleep to experimentally control the extent of forgetting? To tackle these questions, a range of techniques including intracranial EEG, scalp EEG, MEG, fMRI, non-invasive brain stimulation (NIBS), and behavioural testing are used.

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.

348
Category:
Computational Biology
Project:

Identifying germline and somatic genetic interactions that are relevant to patient outcomes in cancer

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

Since 2018, several studies have reported “germline-somatic interactions” across cancer types. However, such studies demonstrate extensive heterogeneity in defining the germline and somatic features involved or the specific mechanism of interaction (including predicted protein changes, cell lines/CRISPR screens, and immune system-associated phenotypes), and effectively none evaluate results clinically. We hypothesize that pan-cancer or breast-cancer-specific germline-somatic interactions will demonstrate associations with therapy in the metastatic setting. To test this, we will compile reported (a) germline-somatic variant interactions from papers and (b) datasets with individual-level treatment information and test the associations between these interactions and treatment response in metastatic breast cancer.

346
Category:
Neuroscience
Project:

The neural mechanism underlying multisensory learning during spatial navigation

Project Listed Date:
Institute or Center:
National Institute of Neurological Disorders and Stroke (NINDS)
NIH Mentor:

Dr. Yi Gu

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

Multisensory learning helps an individual learn through more than one sense. However, the underlying neural mechanism is unclear. In this study we aim to pursue this question in a spatial learning regime. We will focus on the medial entorhinal cortex (MEC), which plays a critical role in spatial learning and the dysfunction of which is closely related to Alzheimer’s disease. We will record neural dynamics of the MEC using two-photon imaging approach when mice navigate in virtual environments, in which multisensory spatial information will be precisely delivered. The goal of the project is to deeply understand how the neural response of the MEC contributes to multisensory learning.

345
Category:
Virology
Project:

HIV-1 Env incorporation and maturation

Project Listed Date:
Institute or Center:
National Cancer Institute (NCI)
NIH Mentor:

Dr. Eric Freed

UK Mentor:

Prof. Peijun Zhang

University:
Oxford
Project Details:

The formation of infectious HIV-1 particles requires the incorporation of Env glycoproteins during the assembly process, with Env mediating binding of newly released virions to target cells and subsequent entry via fusion between viral and target-cell membranes. The interaction between the MA domain of Gag and gp41 of Env plays a central role in Env incorporation into virions and in the activation of Env fusion activity, yet this interaction remains poorly understood at the biochemical and structural levels. In addition, recent structures of the MA lattice in both immature and mature HIV-1 particles implicate a maturation-induced rearrangement of MA the lattice. This opens the possibility that MA-gp41 interactions are dynamic, and change during the maturation process.

We aim to apply an array of biochemical, structural, super-resolution imaging, and virological approaches that will interrogate the MA/gp41 interaction and will provide novel insights into the mechanism and dynamics of Env incorporation into HIV-1 particles. A set of informative mutants, which display stabilized MA-MA and/or MA-gp41 interactions, will be used for structural studies,. Cryo-ET analysis of intact mature and immature virions will be performed to obtain structural data that will complement the information obtained with the MA/Gag assemblies. Predictions regarding potential sites of MA-MA and MA-gp41 interactions obtained from these structural studies will be tested in Env incorporation and virus replication assays. This combination of structural, biochemical, and virological studies will help to elucidate the mechanism of Env incorporation into HIV-1 particles and the subsequent process of particle maturation.

344
Category:
Virology
Project:

Imaging HIV-1 nuclear import by in situ cryo-tomography and correlative microscopy

Project Listed Date:
Institute or Center:
National Cancer Institute (NCI)
NIH Mentor:

Dr. Vinay Pathak

UK Mentor:

Prof. Peijun Zhang

University:
Oxford
Project Details:

Human immunodeficiency virus type 1 (HIV-1) is the causative agent behind acquired immunodeficiency syndrome (AIDS) that currently has no cure or vaccine. While antiviral treatments are effective, the rise of drug-resistant strains has become a growing concern. HIV-1 primarily infects the immune system, targeting CD4+ T cells and macrophages and is a lentivirus known to be able to infect non-dividing cells, requiring it to exploit nuclear import mechanisms. This process is dependent on the viral capsid. The HIV capsid is a conical structure that houses the genomic material of the virus. It needs to be metastable in order to be protective while allowing timely disassembly (termed uncoating) to release its genome. The dynamics of the capsid nuclear import and uncoating are still unknown and are modulated by host dependency and restriction factors.

We aim to apply multi-imaging modalities to investigate uncoating and nuclear import of HIV. These will include super-resolution fluorescence microscopy (including the newest MINFLUX technology), Focused Ion Beam and Scanning electron microscopy (cryoFIB/SEM), cryo-electron microscopy and cryo-electron tomography (cryoEM/ET). The viral core and host factors will be fluorescently tagged, and infection will be monitored from viral attachment to nuclear import. The sample will be cryo-preserved and imaged by cryoEM/ET and cryoFIB/SEM. The combination of these imaging techniques, paired with molecular biology and virology tools, will yield unparalleled knowledge of the HIV infection process within the native cells, providing the framework for development of novel therapeutics targeting HIV infection in the future.

343
Category:
Computational Biology
Project:

Computational investigation of tumor microenvironment

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

We are interested in a variety of topics related to “Deciphering cellular heterogeneity in tumor microenvironment using single cell data”, “Functional characterization of tumor infiltrating T cells”, “Links between embryonic development and cancer”, “Functional characterization of non-coding somatic mutations”, and “Methods for single cell omics”. These projects involve non-trivial  methods development as well as sophisticated data analysis but the focus is always on the biological question. Our lab is involved in several collaborations with immunologists and cancer biologists.

341
Category:
RNA Biology
Project:

RNA regulation of lymphocyte activation and immunity 

Project Listed Date:
Institute or Center:
National Cancer Institute (NCI)
NIH Mentor:

Dr. Eugene Valkov

UK Mentor:

Prof. Martin Turner

University:
Cambridge
Project Details:

Lymphocytes respond to infection by rapidly increasing and decreasing the expression of many genes in a highly regulated manner. This regulation requires the integration of transcription, mRNA decay and translation. We are only just beginning to understand how these processes are integrated with each other.  The host labs are studying how the multiprotein CCR4-NOT complex and its associated RNA binding proteins control gene expression. By combining structural and molecular biology approaches with cellular immunology and mouse models of immune responses we offer a broad training experience and the opportunity to discover fundamental mechanisms of gene regulation in the immune system.
 

References:

The RNA m6A binding protein YTHDF2 promotes the B cell to plasma cell transition. Turner, D.J. Saveliev, A., Salerno, F., Matheson, L.S., Screen, M., Lawson, H., Wotherspoon, D., Kranc, K.R, & Turner, M. (2021). bioRxiv. 

Reconstitution of recombinant human CCR4-NOT reveals molecular insights into regulated deadenylation. Raisch, T., Chang, C.T., Levdansky, Y., Muthukumar, S., Raunser, S., Valkov, E. (2019). Nature Communications 10: 3173. 

RNA-binding proteins control gene expression and cell fate in the immune system.  Turner, M., and Díaz-Muñoz, M.D. (2018) Nature Immunology 19:120-129. 

340
Category:
Clinical Research
Project:

Therapeutic effects of microbiome manipulation in the treatment of eczema

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

Dr. Ian Myles

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

Our group focuses on how human health is affected by the normal microorganisms that live on our skin (collectively termed the microbiome). Our emphasis is on eczema (also called atopic dermatitis or AD), which is an inflammatory disease of the skin associated with reduced quality of life and high risk of developing asthma, allergic rhinitis, and food allergies. Recent work has uncovered that the skin microbiome is significantly different between healthy controls and patients with AD and that early commensal diversity may protect against development of AD. These realizations suggest that the skin microbiome contributes to AD presentation through both harmful and protective pathways. Our group identified a species of bacteria from normal healthy skin, called Roseomonas mucosa, which showed promising features in cell culture and mouse models that suggested the bacteria might be able to treat patients with eczema. We have since transitioned into a clinical trial using Roseomonas mucosa as a topical treatment for eczema. 

318
Category:
Developmental Biology
Project:

Understanding the self-organization of morphogenesis and collective cell migration in the zebrafish embryo

Project Listed Date:
Institute or Center:
National Institute of Child Health and Human Development (NICHD)
NIH Mentor:

Dr. Ajay Chitnis 

University:
Cambridge
Project Details:

The posterior Lateral Line primordium is a group of about a hundred cells that migrates under the skin, from the ear to the tip of the tail, periodically forming and depositing sensory organs called neuromasts, to spearhead formation of the zebrafish Lateral Line sensory system. In recent years, this relatively simple and accessible system has emerged as an attractive model for understanding various aspects of morphogenesis in the developing embryo, including the guidance of cell migration, tissue patterning and organ formation. The goal is to use a combination of cellular, molecular, genetic and biomechanical manipulations coupled with live imaging, image processing and the development of multi-scale computational models to understand the self-organization of cell-fate, morphogenesis and migration of the lateral line primordium. Specific focus will be on developing tools and methods for investigating, imaging, quantifying and modelling the mechanics of collective migration, morphogenesis of epithelial rosettes and the intercellular and intracellular signaling networks that coordinate lateral line primordium development.

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