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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.

81 Search Results

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617
Category:
Molecular Biology and Biochemistry
Project:

Large metal-organic cages for encapsulating biomolecules

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

Recent work in the Nitschke group has produced cages potentially capable of encapsulating proteins or nucleic acids. This project will develop the encapsulation of these biomolecules, and study their properties and potential therapeutic applications.

616
Category:
Developmental Biology
Project:

Role of placental exosomes in programming metabolic health via the Placenta-Brain Axis

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

Prof. Susan Ozanne

University:
Cambridge
Project Details:

The placenta is the interface between mother and fetus, integrating signals between the two. There are also a number of pathways linking the placenta to development of the fetal brain, termed the “Placenta Brain Axis”. The placenta releases extra-cellular vesicles (EVs), but the role of these in the placenta brain axis is unknown. EVs are small membrane bound organelles that contain proteins, metabolites and RNA including miRNAs. Placental EV content is regulated in response to the maternal environment and therefore could mediate the known detrimental effects of an in utero obesogenic/diabetic environment on offspring brain development.

This project will explore the underlying mechanisms by which changes in placental EV content can influence the short- and long- term effects on fetal and offspring metabolism via the brain. The project will involve:
(1) profiling of the protein and miRNA content of placental EVs isolated from lean and obese murine pregnancies,
(2) a combination of in vitro and in vivo experiments to establish the functional consequences of the changes in placental EV protein and miRNA content and
(3) labelling of placental EVs to identify the parts of the brain that they fuse with.  

615
Category:
Neuroscience
Project:

The impact of maternal obesity in pregnancy on offspring brain development

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

Prof. Laura Dearden

University:
Cambridge
Project Details:

Maternal over-nutrition and obesity during pregnancy is known to have long-term effects on the health of the offspring, including increased risk of obesity. Weight gain in offspring exposed to maternal over-nutrition is at least in part caused by hyperphagia- implicating altered function of hypothalamic energy homeostatic pathways as an underlying cause- but the precise mechanisms by which the in utero environment impacts on hypothalamic development is unclear. Key metabolic hormones such as insulin, leptin and ghrelin have a dual role during brain development as growth factors. These metabolic hormones are altered in an obese pregnancy, providing a direct route by which the maternal nutritional state can impact on offspring hypothalamic development. We will use a combination of in vivo manipulation of hormone levels (e.g. fetal brain injection) and ex vivo neuro-developmental techniques (e.g. neurospheres) to examine the consequences of altered metabolic hormone levels for early hypothalamic development. We will also use immunofluorescence and viral tracing to study hypothalamic architecture in the offspring of obese mothers once they reach adulthood, and correlate the anatomy with functional readouts of complex feeding behaviours using operant and metabolic chambers.  

614
Category:
Neuroscience
Project:

Assessing the disease severity in CADASIL using patients iPSC-derived models of the neurovascular unit 

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

CADASIL is a hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene. Small vessel diseases affect the small penetrating arteries and brain capillaries and patients often suffer of migraine, ischaemic stroke, and cognitive decline. Despite its severity, no disease-modifying treatments are available to date. Classical pathogenic mechanisms are associated with cysteine gain or loss in NOTCH3 extracellular domain, but recent studies suggest that mutation site and other polygenic influences may affect disease severity.  In the lab, we have developed a human in vitro model using induced pluripotent stem cells (iPSC) from CADASIL patients to identify new modifying factors which can be targeted therapeutically. The main aim of the project is to establish iPSC models of CADASIL patients with mild and severe phenotype recruited at the Cambridge Stroke clinic and use these models for omics analysis, mechanistic studies, and drugs screening. The project includes a number of techniques: 2D and 3D iPSC-based neurovascular unit models, transcriptomic, proteomic, phenotypic and functional cell assays and high-throughput screening.

613
Category:
Stem Cell Biology
Project:

Modelling Human Neurodevelopmental Disease with Cerebral Organoids

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

Prof. David Keays

University:
Cambridge
Project Details:

The human brain is arguably the most complex structure in biology. It’s construction is dependent on a complex cascade of cellular events that include mitotic division, relocation of migrating neurons, and the extension of dendrites and axons. These processes are reliant on a dynamic and functionally diverse microtubule cytoskeleton. Microtubules form the mitotic spindle enabling the separation of sister chromatids, they facilitate translocation of the nucleus and extension of the leading process during neuronal migration, and microtubule polymers extend and maintain large and longstanding axons in mature neurons. Reflecting their importance mutations in genes encoding for tubulin subunits and microtubule associated proteins cause severe neurodevelopmental disorders. For instance, variants in TUBA1A are known to cause lissencephaly and cerebral palsy, mutations in TUBB2A cause cortical malformations, and substitutions in MAST1 cause microcephaly, autism and corpus callosum phenotypes. To study the underlying molecular and cellular mechanisms of these diseases the Keays laboratory is exploiting iPSCs and advanced 2D and 3D neuronal cultures. This project will utilise our recently created biobank of patient derived iPSCs (http://www.tubulinbiobank.org), coupled with CRISPR-cas9 genome engineering to generate isogenic controls. This project with focus on TUBB2A which is known to cause abnormal cortical gyration, microcephaly,  and/or autism. Following the generation of cerebral organoids, the student will study how disease causing mutations influence the properties of the microtubule cytoskeleton, and the cellular events necessary for brain formation.

Hypothesis:
1)    Mutations in TUBB2A act by altering the assembly, stability and/or dynamics of microtubules.
2)    Microtubule dysfunction perturbs the generation and/or the migration of neurons causing neurodevelopmental disease.

612
Category:
Immunology
Project:

Harnessing gene therapy to treat respiratory inflammation

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

Prof. Adrian Liston

University:
Cambridge
Project Details:

Tissue inflammation is a critical response for the front line of infections. However this same inflammatory response within the tissues is also potentially the most damaging – causing destruction to tissue cells and impeding the physiological functions of the tissue. The actions of immunosuppressive cell types, most potently regulatory T cells (Tregs) can counter this destructive inflammation, but the numbers of these cells within the tissues are limiting (Liston and Gray, Nature Reviews Immunology 2014). Through the use of gene therapy vectors we can deliver potent biologics that either enhance the number of immunosuppressive cell types, or replicate their function, within a tissue. We previously used this approach to create an anti-inflammatory pro-repair environment in the brain, protecting against brain inflammation (Yshii et al, Nature Immunology 2022) and aging (Lemaitre et al, EMBO Mol Med 2023). We have developed a novel system of gene delivery that allows an analogous correction of inflammation within the lung, with potential use in respiratory infections, and non-infectious inflammatory diseases. The proposed project will work on identifying the optimal biologics to deliver to the lung to drive repair during inflammation, will test the novel treatment in mouse models of respiratory disease, and will initiate testing in human lung tissue.

611
Category:
Developmental Biology
Project:

Elucidating the role of pioneer transcription factors in human lung airway differentiation

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

Dr. Emma Rawlins

University:
Cambridge
Project Details:

We have recently identified a human airway epithelial progenitor cell expressing high levels of the pioneer transcription factor ASCL1. Our data suggest that these cells are key progenitors during lung development, and we hypothesize that ASCL1 plays an important functional role. We have recently constructed a single cell RNAseq atlas for the developing human lung and predicted the differentiation trajectories (He et al. 2022), many of which differ to those seen in mice. We have also established a human foetal lung organoid system in which the progenitor cells generate heterogeneous progeny (Lim et al., 2023). This organoid system provides an ideal, dynamic model to test hypotheses regarding lineage relationships and progenitor cell function during human lung development.   We will test the hypothesis ASCL1 is necessary for efficient airway differentiation. We propose to use our lung organoid systems, in conjunction with an effective genetic toolbox recently established in our lab for human organoids (Sun et al. 2021) to knock-down ASCL1 transcription. We will also use targeted damID (Southall et al., 2013; Sun et al., 2022) to assess the binding targets of ASCL1 in progenitor cells and during the differentiation of specific lineages.    

He et al., 2022. “A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates.” Cell 185: 4841-4860, doi.org/10.1016/j.cell.2022.11.005  

Lim et al., 2023 “Organoid modelling of human fetal lung alveolar development reveals mechanisms of cell fate patterning and neonatal respiratory disease.” Cell Stem Cell, 30: 20-37, doi.org/10.1016/j.stem.2022.11.013

Southall et al., 2013. “Cell-type-specific profiling of gene expression and chromatin binding without cell isolation: assaying RNA Pol II occupancy in neural stem cells.” Dev Cell, 26: 101-112, doi.org/10.1016/j.devcel.2013.05.020

Sun et al. 2021. “A Functional Genetic Toolbox for Human Tissue-Derived Organoids.” ELife 10 (October). https://doi.org/10.7554/eLife.67886  Sun et al., 2022. “SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling.” EMBO J, 41, e111338, doi.org/10.15252/embj.2022111338

610
Category:
Neuroscience
Project:

Single-cell approaches to understand neuronal vulnerability to mitochondrial dysfunction

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

Mitochondria are present in every nucleated cell and perform many essential functions. Their primary role is the efficient generation of adenosine triphosphate (ATP) which is required for all active cellular processes including protein synthesis, cell growth and repair. Mitochondrial dysfunction is seen in many common and rare diseases, but given their central role in cell homeostasis, it remains puzzling why this targets some cell-types and not others. We have developed new single-cell methods allowing us to address this question by studying tens of thousands of cells in the brain over the life course. This will cast light on the role of mitochondria in human ageing and neurodegenerative diseases.

609
Category:
Virology
Project:

Elucidating Roles of Biomolecular Condensates in Replication and Assembly of RNA Viruses 

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

Dr. Alex Borodavka

University:
Cambridge
Project Details:

There is a need for new drugs to combat viruses that threaten our health. Most existing antivirals inhibit virus attachment/entry or target critical enzymes, and new antiviral targets are needed to develop novel treatments and counter antiviral resistance. One key process in the life cycle of many viruses is the formation of dynamic organelles called viral factories. There is increasing evidence that some viral factories form via liquid-liquid phase separation (LLPS), including SARS-CoV-2, influenza, and measles virus. These compartments concentrate viral replication enzymes and sequester replication intermediates from the immune sensors. Targeting the physicochemical process of phase separation is an emerging paradigm that may underlie the discovery of novel, broad-spectrum antivirals, but this can only be realised by first understanding how viral factories form. This research project will focus on dissecting the physicochemical properties of these viral condensates to understand how their dynamic conformations and posttranslational modifications that affect charge mediate assembly of viral factories, and in doing so, identify targets for future therapeutic intervention. To quantitatively describe the formation of these condensates, we will examine the observed phase transitions of binary and tertiary mixtures of recombinantly produced viral proteins, as well as viral RNAs in vitro using the recently developed high-throughput microfluidics platform PhaseScan. These findings will lead us to define a new model of viral replicative condensate formation that addresses protein-specific attributes (posttranslational modifications, conformation), and their highly selective RNA composition (partitioning of cognate viral transcripts and exclusion of non-viral RNAs). The insights gained from these approaches will underlie the search for compounds that could serve as drug templates for prospective therapies for RNA viruses and improve our fundamental understanding of the synergistic interactions of viral proteins that spontaneously form complex condensates that are involved in viral replication.

This project will provide an excellent research environment that will foster the future development of the PhD candidate through extensive multi-disciplinary training in
i) microfluidics;
ii) protein biochemistry;
iii) biophysics of condensates;
iv) machine learning approaches required for bespoke data analyses.

This project will provide a unique training environment required for training next-generation biochemists interested in exploring biomolecular condensates and their roles in viral replication and assembly, with an ultimate goal of identifying new druggable antiviral targets.

588
Category:
Cancer Biology
Project:

Understanding cancer clonal dynamics towards novel therapeutic approaches

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

Dr. Sam Mbulaiteye

University:
Cambridge
Project Details:

Burkitt lymphoma (BL) is an aggressive cancer of germinal centre B cells that largely affects children globally. In sub-Saharan Africa, Burkitt lymphoma is an endemic disease associated with Epstein-Barr Vius (EBV) and Plasmodium falciparum infection. Unfortunately, children in sub-Saharan Africa have a far worse outcome with about 40% of children surviving compared to greater than 90% elsewhere, particularly in high income countries in Europe and North America. This is due to low access to reliable pathology diagnosis, limited access to specialized oncology centres, where the effective cytotoxic treatments and necessary life support can be given to patients during care. However, there might be biological factors that contribute as well to differences in outcome> For example, Burkitt lymphoma in sub-Saharan Africa is associated with EBV and Plasmodium falciparum infection, which may mediate a different tumour landscape (predominated by action of mutator enzyme adenosine-induced cytosine deaminase), whereas elsewhere these factors are lacking and the tumour landscape is influenced by accumulation of mutations in genes influencing apoptosis. In Cambridge, Prof. Turner has developed in vivo models of both sporadic and endemic Burkitt lymphoma that facilitate comparative research into disease mechanisms. In this project, these will be employed to understand the clonal heterogeneity of these malignancies using a combination of in vivo CRISPR screens and lineage tracing. Data will be validated using a large resource of primary patient specimens available within the EMBLEM study coordinated by the National Cancer Institute. Ultimately, data will be analysed with a view to developing biomarkers of disease prognosis as well as novel therapeutic approaches. In both cases the resource settings of sub-Saharan Africa will be considered towards sustainable and achievable approaches. The student will have the opportunity to travel to Uganda during the course of their studies.

465
Category:
Virology
Project:

Quantitative proteomic analysis of the host-pandemic virus interaction

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

Evolution has produced an arms race between viruses and the cells they infect. Studying this battle provides key insights into cell biology and immunology, as well as the viruses themselves. It may even lead to the development of novel therapeutics. The Matheson lab therefore focuses on two pandemic viruses with a major impact on human health: HIV and SARS-CoV-2.  

We have previously used unbiased proteomics to quantify dysregulation of hundreds of proteins and processes in infected cells, and now aim to understand the importance of these targets for both viral pathogenesis and normal cellular physiology. Because HIV regulates numerous cell surface amino acid transporters, we are particularly interested in amino acid metabolism and protein biosynthesis.  

Depending on the interests of the student, this project will therefore focus on either (1) an orphan cell surface amino transporter downregulated by SARS-CoV-2 infection of respiratory epithelial cells or (2) an ancient metabolic enzyme regulating ribosomal frame shifting depleted by HIV infection of primary human CD4+ T cells.  

In either case, the aims will be to: validate the target in different systems; define the mechanism of viral regulation; determine the functional effects of target depletion in biochemical and cell biological assays; and characterise the impact of target depletion on viral infection. Opportunities will be available to conduct further proteomic screens, perform ribosomal profiling and/or stable isotope-based metabolomics.   

The project will provide training in a wide range of molecular and biochemical techniques, whilst allowing the student to explore an important aspect of the host-virus interaction. The Matheson lab is based in the brand new Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), including the largest academic Containment Level 3 (CL3) facility in the UK. The student will be supervised by an experienced postdoc in a friendly, supportive group. 
 

435
Category:
Neuroscience
Project:

The role of GABAergic inhibitory interneurons during visually-guided decision-making

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

Prof. Jasper Poort

University:
Cambridge
Project Details:

The brain is continuously bombarded with visual input but has limited processing capacity. Learning to selectively process visual features relevant for behaviour is therefore crucial for optimal decision-making and thought to rely on activity of GABAergic inhibitory interneurons. Altered inhibition is linked to perceptual and learning impairments and associated with neurodevelopmental disorders including schizophrenia and autism.

The aim of this project is to understand the precise role of different types of GABAergic inhibitory interneurons during visually-guided learning and decision-making. Mice have a similarly organized visual cortex and show complex decision-making behaviours. Mouse brain circuits can be measured and manipulated during behaviour in ways not possible in humans.

Our approach is to train mice, including pharmacological and genetic mouse models of neurodevelopmental disorders and healthy controls, in visual decision-making tasks. We measure activity in visual cortex in specific cell types using 2-photon imaging and electrophysiology and use optogenetics to activate or inactivate activity of specific interneuron cell types. We will also apply two new innovative methods to optically measure the inhibitory neurotransmitter GABA (developed in the Looger lab, UCSD) and to locally pharmacologically manipulate GABA levels in the brain (collaboration with Malliaras and Proctor labs, Dept of Engineering, Cambridge) during visual learning and decision-making.

The PhD project is associated with a Wellcome Trust funded Collaborative programme with a cross-disciplinary international research team to investigate the role of GABAergic inhibition in both mice and humans at different scales, from local circuits to global brain networks.

Lab website: https://www.pdn.cam.ac.uk/svl
Contact: Jasper Poort jp816@cam.ac.uk

432
Category:
Computational Biology
Project:

Artificial intelligence in diagnostic prostate MRI to improve outcomes

Project Listed Date:
Institute or Center:
National Cancer Institute (NCI)
University:
Cambridge
Project Details:

There has been increasing interest in applying computational methods in medicine, to make sense of cancer’s ‘big data’ problem by exploiting recent advances in data-processing and machine learning to capture and integrate clinical, genomic, and image data collated from hundreds of cancer patients in real-time. Such methods can be applied to digital clinical images to extract image information about patterns of pixels that are not perceivable to the human eye, allowing characterisation of tumour.  Prostate cancer is the 2nd commonest male cancer worldwide, and MRI is the diagnostic tool of choice, however, MRI can miss 10% of significant tumours and leads to unnecessary (invasive) biopsy in around 1/3rd patients who do not have cancer.  

We will use a prototype AI system (Pi) developed with Lucida Medical on retrospective data, in a prospective clinical study. We plan to link histological data to imaging features derived from MRI (including texture analysis) to identify predictors of lesion aggressiveness and need for sampling, using biopsy cores and surgical specimens from the prospective cohort. Further work will link biopsy tissue to MRI data to identify radiogenomic markers of disease aggressiveness. The project presents an opportunity for AI to answer key clinical questions at the intersection of interpretation, imaging and biopsy.  

The project will involve working with
an established interdisciplinary programme of researchers and help in the assessment of cross-cutting “multi-omic” approaches to cancer assessment, involving integration of advanced image analysis, transcriptomic, genomic, tissue, and patient outcomes to inform the design of diagnostic strategies.

431
Category:
Structural Biology
Project:

Self-assembling multi-functional biomolecular condensates for targeted degradation of disease-associated proteins 

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

We are developing artificial multi-valent proteins capable of liquid-liquid phase separation (LLPS) with the aim of building multi-functional biomolecular condensates and thereby harnessing specific cellular enzymes to target disease-associated proteins for destruction. We propose to design condensates that contain a class of proteins known as tandem-repeat proteins (RPs). We have shown that RPs are strikingly amenable to rational design and can be engineered to simultaneously bind multiple proteins, bringing them into specific spatial proximity in such a way as to enable a chemical modification of the target protein. The rational design of LLPS systems capable of selectively recruiting client proteins into them to drive specific biological reactions would enable both a deeper understanding of the role of biomolecular condensates in nature as well as the exploitation of their remarkable physico-chemical properties for therapeutic effect. 

Key areas of interest include: 
 

  1. Understanding the molecular grammar of protein phase separation to define rules for creating designer LLPS systems. 
  1. Developing novel hetero-bifunctional phase-separating proteins to recruit disease-associated targets to the protein degradation machinery. 
  1. Translating the designed LLPS proteins into biomolecular condensates in the cell capable of enhancing targeted protein degradation. 
430
Category:
Microbiology and Infectious Disease
Project:

Investigating the evolutionary trajectories of P. aeruginosa

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

Prof. Martin Welch

University:
Cambridge
Project Details:

“Life will find a way….” In a now famous quote from the 1993 movie Jurassic Park, the “chaotician” Ian Malcolm nicely captures the essence of adaptation through evolution. But series evolutionary change often requires multiple mutations to arise – the changes arising from SNPs and indels in single genes usually amount to little more than phenotypic “tinkering”. So what would happen if we could “step on the evolutionary gas pedal” and accelerate the pace of change? Or alternatively, what would be the consequences of “slamming on the evolutionary brakes” to prevent adaptation? Well, these are just the kind of approaches that we have developed in the Welch lab, and we are applying these to look at how the opportunistic bacterial pathogen, Pseudomonas aeruginosa, adapts to the presence of infection-relevant selection pressures. Essentially, we’ve engineered the mismatch-repair system to come under the control of an inert chemical inducer, and so can “rheostatically” modulate the rate of mutation from very high (1000 x the wild-type level) to very low indeed (eliciting a state of “hypomutation” in which evolutionary change essentially grinds to a halt).

Using this system, we aim to investigate the evolutionary trajectories of P. aeruginosa when challenged with intense selection pressures e.g., in a polymicrobial environment, or upon exposure to antimicrobial agents or nutrient limitation. Project will involve elements of synthetic biology, microbiology, evolutionary biology, modelling and genomics. A stable polymicrobial culture system has recently been developed by the lab and is available for use.  

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