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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.

16 Search Results

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447
Category:
Cell Biology
Project:

Analysis of APP and Tau function in exosome and supermere secretion and signalling

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

Prof. Clive Wilson

University:
Oxford
Project Details:

Aggregations of the cytoskeletal protein Tau into neurofibrillary tangles and cleavage products of the Amyloid Precursor Protein (APP) into amyloid plaques are strongly associated with the progression of Alzheimer’s Disease (AD). However, it remains unclear whether these aggregates initiate and cause disease or are primarily by-products of more fundamental defects. Furthermore, the physiological and cellular roles of Tau and APP, which might be disrupted in AD, are not well understood.

We have developed a new cell model in the fruit fly, Drosophila melanogaster, to study the normal functions of fly APP and Tau. Remarkably, we find that they are both involved in the biogenesis and secretion of two multimolecular signalling complexes, which are formed in endosomes: exosomes, which are small secreted vesicles, and supermeres, newly identified aggregates of protein and RNA. Their secretion is disrupted when pathological versions of Tau or cleaved APP are expressed in these cells. Using the fly model, we have already identified multiple additional regulators of these APP- and Tau-dependent processes, some of which are implicated in other neurodegenerative diseases. This project will employ neuronal and cancer cell lines to investigate which of these mechanisms are conserved in human cells and how they affect both exosome and supermere signalling. Again, informed by genetic screens in flies, we will then test whether Tau- and APP-induced defects in secretion are suppressed by genetic manipulations of other genes, which might provide new therapeutic targets going forward.

444
Category:
Cell Biology
Project:

Identifying novel targets to treat and prevent arterial disease

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

Prof. Nicola Smart

University:
Oxford
Project Details:

Progression of arterial disease is critically determined by the response of smooth muscle cells (SMCs) within the medial layer. In their fully differentiated, contractile state, SMCs confer stability and regulate vascular tone. However, disease induces a ‘contractile-synthetic’ phenotypic switch which impairs function, leads to vascular stiffness and exacerbates inflammation, to promote atherosclerosis and susceptibility to abdominal aortic aneurysm (AAA) (1). In animal studies, we have identified candidate pathways, based on knowledge of embryonic SMC differentiation, with the potential to protect against AAA1 and atherosclerosis (2) by preserving contractile SMC phenotype. However, the low success rate in translation from animal studies to the clinic highlights the need to determine whether similar mechanisms serve to protect the human vasculature, and how they may be targeted to alleviate disease.

The aim of the project is to establish human-relevant SMC models in which to study phenotypic switching and disease: i)
a monoculture of human coronary artery SMCs; the simple monoculture model will permit evaluation of factors that directly impact SMC modulation, without confounding influences of other cell types.  ii) a more physiologically relevant model of hcSMCs co-cultured with coronary arterial endothelial cells. EC-SMC interaction crucially maintains vascular tone and functionality and dysregulation of this crosstalk underpins pathological remodelling e.g. in intimal hyperplasia. These models will then be used for high genetic and pharmacological screening to reveal disease-modifying targets. The most promising will be explored in murine disease models.

 

1). Munshaw et al. (2021) J Clin Invest 131.(10):e127884.

2). Munshaw, Redpath, Pike & Smart. bioRxiv, 2021.2011.2030.470548 (2021).

438
Category:
Cell Biology
Project:

Investigating the beneficial role of OXPHOS during regeneration

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

In contrast to patients after myocardial infarction, fish can fully regenerate their hearts. However, not all fish are able to regenerate to the same extent, allowing comparative inter- and intra-species analysis to identify novel mechanisms controlling successful heart regeneration. We have compared the response of seven different wild type zebrafish strains as well as Astyanax mexicanus surface and cavefish to cryo-injury. Preliminary data shows that there are large differences in regeneration within each species. Using RNAseq, we have identifed OXPHOS as a crucial regulator of this difference with increased OXPHOS being beneficial to long term regeneration. This finding indicates that the current stance in the field, that OXPHOS is damaging the ability for heart regeneration, needs to be re-evaluated.

In this project, we will investigate the mechanisms underlying the beneficial role of OXPHOS during regeneration and the techniques you will perform are targeted metabolomics, QTL analysis, RNAseq and Electron Microscopy. As the human heart relies on OXPHOS for energy, the findings from this project could help identify therapies that can direct OXPHOS to enhance cardiomyocyte proliferation and harness the potential of the human heart to regenerate.

427
Category:
Cell Biology
Project:

Role of vascular smooth muscle cells (VSMCs) in cardiovascular disease

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

Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of cardiovascular diseases such as atherosclerosis, which cause heart attack and stroke. In healthy vessels, VSMC contraction regulate blood flow and blood pressure but loose their contractile function and undergo extensive transformation upon vasuclar insult. This process results in the generation of a wide spectrum of phenotypically changed cells within atherosclerotic lesions, which are predicted to impact differently on disease progression. Using clonal lineage tracing in mouse models of atherosclerosis, we demonstrated that disease-associated cell accumulation result from extensive proliferation of a small subset of VSMC that can generate the full range of distinct cells. By combining lineage tracing with single cell RNA sequencing (sc-RNAseq) in mouse models, we have identified signatures of VSMC-derived cells subpopulations. Interestingly, cells displaying mesenchymal stem cell character are rare in healthy vessels and their numbers increase in disease models. The aim of this project is to understand how specific VSMC-derived cell populations in human disease arise, using a combination of genomics and functional assays, in order to allow efficient cell targeting in atherosclerotic lesions.

426
Category:
Cell Biology
Project:

Understanding placental peptide hormones

Project Listed Date:
Institute or Center:
National Institute of Environmental Health Sciences (NIEHS)
NIH Mentor:

Dr. Carlos M. Guardia 

University:
Cambridge
Project Details:

The human placenta is the first organ of the embryo and it is functional immediately after implantation. Before fetal organogenesis, the placenta holds a multi-functional and unique role as a physical, chemical, and cellular barrier. It alone orchestrates the chemical communication between mother and fetus. Most of this communication is mediated by the secretion of specific placental peptide hormones (hCG, hPL, etc.) into the maternal bloodstream. Despite these hormones having developmental and irreplaceable functions, little is known about their intracellular life: synthesis, intracellular traffic, secretion, and degradation. More importantly, many pregnancy disorders are associated with lower expression and levels of these hormones in circulation, such as fetal growth restriction and preterm birth. The cell biology of these diseases is not well understood.

With the recent advance in human placenta organoid development and novel culture techniques of trophoblasts derived from stem cells, we can now finally interrogate the fundamental questions about placental hormones' intra and extra-cellular fate. In combination with the diverse set of advanced imagining methods available between the co-mentors of this project (advanced fluorescence and cryo-electron microscopy), innovative multi-omics techniques, and advanced biochemistry and cell biology approaches, we propose to 1) discover the diversity of secretory granules (SGs) expressed in and secreted from the human placenta; 2) implement a novel in vitro secretomics approach to determine the molecular machinery that regulates the secretion of the SGs and their content; 3) validate the mechanisms using human placenta and isolated trophoblasts from donated tissue and new placenta organoids culture.

The successful candidate will have the opportunity to train on several modern imaging techniques and learn about the fundamentals of placenta development and physiology while using a multi-disciplinary approach in a team of expert cell biologists from both institutions and generating impactful basic and applied research.

421
Category:
Cell Biology
Project:

Developmental origins of tissue-specific vulnerability to mitochondrial disease

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

Mitochondrial diseases are caused by defects in genes required for energy production and oxidative phosphorylation (OxPhos). We find it intriguing that some patients with mitochondrial disease present late in life, with very tissue-specific phenotypes. It seems that not all cells and tissues are equally susceptible to mitochondrial disease.

We mainly study how mitochondrial dysfunction and mutations in the mitochondrial genome affect neural stem cell behaviour in Drosophila and mouse. The questions we address are:
(1) how mitochondrial dysfunction affects normal and pathological cell fate decisions in the developing brain. We previously showed that neural stem cells in the brain rely heavily on mitochondrial energy production and now study how they interact with the glial cells that make up their stem cell niche.
(2) how transcription of the nuclear genome is regulated when a cell is confronted with mitochondrial dysfunction. We employ and develop innovative DamID-based in vivo chromatin profiling technology to study metabolism of chromatin modification.
(3) how mutations in the mitochondrial genome evolve over time, during brain development and aging. We use in situ hybridisation-based methods and single-cell CRISPR screening to identify novel regulators of mitochondrial genome maintenance.

In order to study these questions in an in vivo context, in (stem) cells surrounded by their appropriate tissue environment, our primary model system is the fruit fly, Drosophila melanogaster. In addition, we actively translate our findings and the technology we develop into mammalian model systems, in particular the mouse embryonic cortex.

Relevant references
- van den Ameele J, Krautz R, Cheetham SW, et al., Reduced chromatin accessibility correlates with resistance to Notch activation. Nat Commun. 2022;13(1):2210.
- van den Ameele J, Li AYZ, Ma H, Chinnery PF. Mitochondrial heteroplasmy beyond the oocyte bottleneck. Semin Cell Dev Biol. 2020 Jan. 97:156-66.
- van den Ameele J, Brand AH. Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation. eLife. 2019;8:e47887.
- Tiberi L*, van den Ameele J*, Dimidschstein J, Piccirilli J, Gall D, Herpoel A, Bilheu A, Bonnefont J, Iacovino M, Kyba M, Bouschet T, Vanderhaeghen P. Bcl6 induces neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets. Nat Neurosci. 2012 Dec;15(12):1627-35.
- Gaspard N, Bouschet T, Hourez R, Dimidschstein J, Naeije G, van den Ameele J, Espuny-Camacho I, Herpoel A, Passante L, Schiffmann SN, Gaillard A, Vanderhaeghen P. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature. 2008 Sep 18;455(7211):351-7.

229
Category:
Cell Biology
Project:

Develop and apply new super-resolution fluorescence and electron microscopy methods to the study of membrane traffic

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

Dr. Justin Taraska

UK Mentor:

Prof. Sean Munro

University:
Cambridge
Project Details:
N/A
203
Category:
Cell Biology
Project:

Computational investigation of ligand-binding with a particular emphasis on membrane proteins

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

Prof. Philip Biggin

University:
Oxford
Project Details:
N/A
202
Category:
Cell Biology
Project:

Understanding how membrane-bound organelles form and acquire their distinctive proteome

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

My lab is interested in understanding how membrane-bound organelles form and acquire their distinctive proteome essential to carry their specialized functions. In particular, we focus on how organelle function is maintained through quality control processes, such as protein degradation. We are also interested in inter-organelle communications- which and how molecules are exchanged between organelles, which signals regulate those exchanges, etc.  Although my lab does mostly basic research, we are interested how these processes are disrupted in human disease.

181
Category:
Cell Biology
Project:

Mechanisms controlling organelle dynamics and quality control

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

Prof. Pedro Carvalho

University:
Oxford
Project Details:

Our lab is interested in membrane-bound organelles- how they form and acquire their distinctive proteome essential to carry their specialized functions. In particular, we focus on how organelle function is maintained through quality control processes. Our lab has been particular interested in a quality control process termed ERAD, which targets misfolded membrane proteins in the endoplasmic reticulum (ER). While some of the components of this process have been identified, the mechanisms by which diverse range of misfolded proteins are selected, ubiquitinated, extracted from the ER membrane and targeted for degradation by the proteasome remain elusive. To gain insight on the mechanisms of protein quality control our lab is taking multidisciplinary approaches. We are using CRISPR-based genome-wide genetic screens to delineate the molecular pathways involved in the degradation of disease-relevant misfolded proteins. In parallel, we use biochemical, proteomics and structural approaches to dissect mechanistically the multiple steps of ERAD. These studies will reveal the molecular basis of quality control processes by which misfolded and aggregation-prone proteins are handled by the cell both under normal and pathological situations. We are also interested in inter-organelle communications- which and how molecules are exchanged between organelles, which signals regulate those exchanges, etc.  Although we do mostly basic research, we are interested how these processes are disrupted in human disease.

157
Category:
Cell Biology
Project:

The tubulin code in health and disease

Project Listed Date:
Institute or Center:
National Institute of Neurological Disorders and Stroke (NINDS)
University:
Oxford
Project Details:
N/A
101
Category:
Cell Biology
Project:

Molecular organization of axons and dendrites

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

Dr. Naoko Mizuno

UK Mentor:

Prof. Andrew Carter

University:
Cambridge
Project Details:

Neurons are specially shaped cells that have an extremely polarized structure. They contain protrusions called dendrites and a long axon extending from cell body that connect to neighbouring cells forming a neural network. Axons and dendrites retain a dynamic plasticity throughout the whole lifespan of a neuron to ensure the ability to adjust and adapt neural network connections.  The polarity and plasticity of neurons is maintained by a cytoskeleton of actin filaments and microtubules together with associated motors and other essential proteins.

 

This PhD project aims to elucidate the molecular organization of axons and dendrites using in situ cryo-electron tomography (cryo-ET) of primary neurons.  We will address how cytoskeletal filaments and motors drive the branching, elongation and neural network formation. To this end we form a strong collaboration between the lab of Andrew Carter at the Laboratory of Molecular Biology (LMB), Cambridge University and Mizuno Naoko at the National Heart, Lung and Blood Institute at NIH. Mizuno’s lab’s expertise is visualizing cell shape formations controlled by remodelling of cytoskeleton and the Carter lab has a long-standing interest in how trafficking is carried out by cytoskeletal motors.

 

Cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) bridge the resolution gap between light-microscopy and conventional structural methods for gaining information on a molecular level (X-ray crystallography/NMR).  Current technical developments further facilitate in-depth analysis of cells on a molecular level that has not been possible before. The skillset obtained in this PhD project will be highly relevant to the field of newly emerging structural cell biology.

100
Category:
Cell Biology
Project:

Crosstalk of the cell-surface membrane system

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

Dr. Naoko Mizuno

UK Mentor:

Prof. Yvonne Jones

University:
Oxford
Project Details:

The formation of neural network is essential for building a nerve system and to maintain its dynamic function. Neuronal cells extend their axons to connect to dendrites of partner neurons. The process is facilitated by axonal migration and controlled by the balance of the search for partner neurons vs the locking of axon-dendrite connections. This balance is maintained by two signaling pathways relying on the integrin receptor (mode of neurite migration) and the semaphorin receptor (mode of axon-dendrite locking). The inter-regulation between both pathways is mediated by the intracellular signaling factor Rap1. However, the mechanism of this interconnection is unknown.

 

This PhD project aims to elucidate the nature of this crosstalk using a bottom-up reconstitution of integrin, semaphorin and Rap1 by developing a cell-surface mimicking membrane system. We aim to establish a functional membrane system that allows us to control the two modes, i.e. attachment/detachment of two neighboring membranes representing dendrite and axon connections. The uniqueness of the project lies in the exact control of communication through membranes by the bottom-up strategy, which would be otherwise extremely challenging to elucidate. Moreover, the system will allow us to probe receptor interactions using biophysical, light microscopic as well as cryo-EM methods to understand the underlying principles of neural network formation and neuronal regeneration.

 

Our collaborative team has expertise in a wide variety of interdisciplinary techniques to facilitate the proposed PhD research, such as X-ray crystallography, cryo-EM, biophysical analysis, membrane biology and light microscopy. Mizuno lab is leading in the use of cryo-EM in combination with cellular methods to visualize cell shape formations controlled by the integrin signaling pathway and the remodeling of cytoskeleton components. Jones lab has a long-standing interest in axon guidance and structural biology of membrane proteins. Yvonne Jones co-heads the Structural Biology Division of the Wellcome Centre for Human Genetics at the University of Oxford.

 

This project will give a candidate a tremendous opportunity to apply cutting-edge in vitro reconstitution methods in the field of structural- and neuro- biology.

99
Category:
Cell Biology
Project:

Mitochondrial regulations and their roles in metabolic adaptation in hibernation

Project Listed Date:
Institute or Center:
National Eye Institute (NEI)
NIH Mentor:

Dr. Wei Li

UK Mentor:

Prof. Mike Murphy

University:
Cambridge
Project Details:

Hibernation confers extraordinary protection against various forms of stress and insults that would be life-threatening to non-hibernators. However, the mechanisms of such promising protection remain elusive, hindering potential therapeutic applications. One of the hallmarks of hibernation is metabolic regulation, exemplified by modifications in mitochondrial respiration throughout the different stages of hibernation. Nonetheless, the possible link between metabolic regulation and cellular protection is unclear.  This project aims to study the mitochondrial regulations and their roles in metabolic adaptation during hibernation, in the context of neuroprotection.

98
Category:
Cell Biology
Project:

Developing Treatment Paradigms for Age-Related Macular Degeneration.

Project Listed Date:
Institute or Center:
National Eye Institute (NEI)
NIH Mentor:

Dr. Kapil Bharti

UK Mentor:

Prof. Colin Goding

University:
Oxford
Project Details:

Age-related macular degeneration (AMD) is one of the leading causes of blindness among the elderly affecting over 30 million individuals world-wide. AMD initiates in the back of the eye because of dysfunctions in the retinal pigment epithelium (RPE), a monolayer of cells that maintains vision through maintenance of photoreceptor healthy and integrity. AMD can lead to severe vision loss and blindness in advanced stages – “dry” and “wet” forms. In the dry stage, the death of RPE cells triggers photoreceptor cell death and atrophy of the choroidal blood supply causing vision loss. It is thought that RPE cell death in AMD is triggered by the formation of sub-RPE protein/lipid deposits called drusen. Our recent work shows that drusen formation is initiated by reduced autophagic flux in RPE cells resulting in reduced ability of RPE cells to process intracellular “debris” that eventually gets secreted as drusen deposits. TFEB, a member of MiT family of transcription factors is a known master regulator of autophagy. Here, we propose to investigate the activity of transcription factor TEFB in our AMD cellular models of iPSC-derived RPE cells. We hypothesize that autophagy downregulation is triggered by post-translational changes in TFEB that affect its sub-cellular localization and reduce its transcriptional activity. Here, we propose to identify those changes in TEFB and discover signaling pathways that lead to its altered activity. Lastly, we will test the ability of our recently discovered FDA-approved drugs that stimulate TEFB activity to reduce drusen formation by increasing autophagy in iPSC-RPE AMD models. This work will lead to a better understanding of AMD pathogenesis and potentially retool existing  drugs to treat AMD patients.

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