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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.

241 Search Results

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424
Category:
Developmental Biology
Project:

Maternal over-nutrition and obesity during pregnancy

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

423
Category:
Developmental Biology
Project:

Understanding placental endocrine function in the control of fetal growth and long-term health

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

During pregnancy, nutrients must be supplied to the fetus for growth but also to the mother to maintain the pregnancy. This nutrient balance depends on the placenta, an organ that develops during pregnancy to transfer nutrients to the fetus and that secretes hormones into the mother with metabolic effects. Impaired placental function disrupts the materno-fetal nutrient balance and results in major pregnancy complications, including abnormal birthweight with both immediate and long-lasting effects on offspring health. However, our understanding of the importance of placental endocrine function in the control of fetal growth and long-term health of the offspring is unknown. To address this knowledge gap, we have developed new and robust models of genetically-induced placental endocrine malfunction in mice. Using these models, we have found that placental endocrine malfunction is associated with programmed changes in insulin and glucose handling of both the female and male offspring in adult life.

This PhD will extend these important findings by:
1. Identifying which tissues in the offspring are affected by placental endocrine malfunction and responsible for the altered glucose and insulin handling of offspring in later life.
2. Exploring the intrauterine mechanisms by which metabolic organs of the developing offspring are programmed by placental endocrine malfunction.

This will be achieved by studying the function of key metabolic organs in female and male offspring that were supported by placentas with endocrine malfunction. Particularly, it will use genetic manipulation and a range of in vivo physiological (metabolic testing, NMR scanning), and in vitro molecular (respirometry, RNAseq, western blotting, qPCR, epigenetic analysis), histological and biochemical assays.

422
Category:
Virology
Project:

Identification and characterisation of novel antiviral restriction factors

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

Prof. Mike Weekes

University:
Cambridge
Project Details:

Antiviral restriction factors (ARF) are a critical element of cellular innate immunity, representing the first barrier to viral infection that can determine outcome. We aim to identify and characterise novel ARF and their viral antagonists, since therapeutic interruption of viral antagonism can enable restoration of endogenous antiviral activity.

We employ a number of human pathogens, in particular Human Cytomegalovirus (HCMV), Monkeypox virus (MPXV) and its vaccine, Modified Vaccinia Ankara (MVA). Our systematic proteomic analyses determine which cellular factors each pathogen targets for destruction, since we have shown these to be enriched in novel ARFs. For example, we recently developed a multiplexed proteomic technique that identified proteins degraded in the proteasome or lysosome very early during HCMV infection (Nightingale et al, Cell Host & Microbe 2018). A shortlist of 35 proteins were degraded with high confidence, and we have since shown that several are novel ARF, with characterisation of these factors forming ongoing projects. Application to MVA infection indicated further candidates, and identified novel mechanisms of vaccine action (Albarnaz et al, in review, https://www.researchsquare.com/article/rs-1850393/v1). Furthermore, interactome screens can identify the viral factor(s) responsible for targeting each ARF, and indicate mechanism (Nobre et al eLife 2019).

This project will now identify and characterise critical pan-viral ARF, which can restrict diverse viruses. For the most potent, we will determine both the mechanism of restriction and the mechanism of virally mediated protein degradation. In order to prioritise the most important factors, there will also be the opportunity to use novel multiplexed proteomic screens.

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.

420
Category:
Stem Cell Biology
Project:

Disease pacemaker Stem Cells in Neurodegenerative Disease

Project Listed Date:
Institute or Center:
National Institute on Aging (NIA)
NIH Mentor:

Dr. Isabel Beerman

University:
Cambridge
Project Details:

The presence and role of neural stem cells (NSCs) in the adult human brain is a long-debated issue in neuroscience. Recent work has demonstrated that stem-like cells exist in the embryonic, foetal, and human adult brain where they persist well into adulthood and can even contribute to neurogenesis. However, their role in neurodegenerative disease is unknown. Ongoing work in the lab has led to the hypothesis that NSCs may become dysfunctional in neurodegenerative disease resulting in senescence chronic inflammation, and thereby acting as pacemaker cells driving neuronal demise. This ambitious project aims to identify disease-associated NSCs and their phenotype in the context of human neurodegeneration using spatial biology approaches, including imaging mass cytometry, RNA scope and single nuclear RNA sequencing. Relying on post-mortem brain tissue of different stages of Alzheimer’s disease, traumatic brain injury, vascular dementia and chronic stroke, this project will study NSCs in a range of human diseases characterised by neurodegeneration and neuronal injury. Ongoing work in the lab identifies NSC-specific markers based on transcriptomics and protein profiling experiments in brains with progressive multiple sclerosis, enabling to investigate the distribution of NSCs in a wide range of diseases. Spatial transcriptomics and proteomic approaches will allow to study their phenotype and dysfunction in relation to other cell types and local pathology. This project will shed light on the role of NSCs in neurodegeneration and has the potential to identify an entirely novel mechanism of neurodegeneration in human disease.

This project will be co-supervised by Prof. A. Quaegebeur.

419
Category:
Stem Cell Biology
Project:

Investigating the molecular regulation of hematopoietic stem cell fitness

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

Dr. Stefan Muljo

University:
Oxford
Project Details:

Multipotent self-renewing hematopoietic stem cells (HSCs) support life-long blood system homeostasis and play essential roles in human disease and its therapy. HSC transplantation is an important cell therapy for a range of hematological diseases including immunodeficiencies, beta-globinopathies, and blood cancers. Through their ability for self-renewal and multipotency, HSCs can reconstitute the hematopoietic system following transplantation. Most HSC transplants are performed using allogeneic HSCs but there is also a growing interest in the development and use of autologous HSC transplantation gene therapies for a range of non-malignant blood diseases. A major unresolved question in the field is what regulates the fitness of an HSC. High fitness HSCs display durable and balanced blood system reconstitution activities. By contrast, low fitness HSCs have weak or biased activities. The accumulation of low fitness HSCs is thought to contribute to various disease pathologies and their use in HSC transplantation can result in engraftment failure. Building on research interests in the Muljo lab at the NIH and the Wilkinson lab at the University of Oxford, this project will focus on characterizing transcriptional and post-transcriptional mechanisms regulating HSC fitness. Biological mechanisms identified here will be used to devise new strategies to enhance life-long hematopoietic system health and to improve the safety and efficacy of HSC transplantation therapies.
 

Recent publications:

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. Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3. Genes & Development, 33: 1048–1068. DOI: 10.1101/gad.325100.119.

Wilkinson, A.C., Ishida, R., Kikuchi, M., Sudo, K., Morita, M., Crisostomo, R.V., Yamamoto, R., Loh, K.M., Nakamura, Y., Watanabe, M., Nakauchi, H. and S. Yamazaki. (2019). Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation. Nature, 571: 117–121. DOI: 10.1038/s41586-019-1244-x.

Haney, M.S., Shankar, A., Hsu, I., Miyauchi, M., Palovics, R., Khoo, H.M., Igarashi, K.J., Bhadury, J., Munson, C., Mack, P.K., Tan, T., Wyss-Coray, T., Nakauchi, H., Wilkinson, A.C. Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging. bioRxiv 2022. DOI: 10.1101/2022.07.22.501030

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.

417
Category:
Stem Cell Biology
Project:

Developmental timing in mammalian stem cell models

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

Prof. Teresa Rayon

University:
Cambridge
Project Details:

The Rayon’s lab (www.rayonlab.org) overall aim at the Babraham Institute in Cambridge is to investigate the molecular and metabolic pathways that control biological timing and lifespan. To answer these questions, we work with mouse and human stem cells and embryos and employ a variety of quantitative and genomic techniques. We are looking for applicants that are curious about evolution, developmental biology and embryonic stem cells.

We are interested in the following topics:
1.    Understanding the regulation of enhancer timing. We want to test the existence of species-specific enhancers and their dynamics.
2.    Exploiting genetic variation to investigate dynamics of regulatory networks in stem cell models.  
3.    To develop a high-content imaging assay to screen for modulators of timing. Develop a screen to explore if epigenetic, metabolic, and turnover factors impact the pace of differentiation.

A background on cell culture or molecular biology, as well as skills in bioinformatics or computational approaches would be useful, but ample opportunities for training will be provided.

416
Category:
Microbiology and Infectious Disease
Project:

Mechanisms of dengue virus antigenic evolution

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

Dr. Leah Katzelnick

University:
Cambridge
Project Details:

Dengue viruses continue to circulate endemically through large parts of the globe. Dengue virus is an antigenically variable pathogen, with individuals able to get reinfected numerous times. The risk of severe disease or death is increased in individuals with pre-existing antibodies generated from prior infections. This antibody-dependent phenomenon has complicated efforts to generate vaccines. The proposed research program aims to tackle this complexity through the combination of computational and experimental work in a joint project between the laboratories of Dr. Henrik Salje, a Professor at the University of Cambridge and the head of the Pathogen Dynamics Group and Dr. Leah Katzelnick, who is Chief of the Viral Epidemiology and Immunity Unit at the NIH. These two labs have a long track of working together, especially focusing research on well characterised settings where we have been able to characterise antigenic, genetic and epidemiologic features of dengue within the same communities. We have previously shown that there are long term trends in the antigenic properties of viruses circulating in the same location, suggesting of evolutionary pressures from local immunity. However, the exact immune and genetic mechanisms remain unknown.

In this PhD project, we will use computational approaches to identify candidate amino acid sites that are linked with shifts in antigenic space and to track these changes over a 30 year period. We will then experimentally test the antigenic movement of viruses mutated at the candidate locations. Finally, we will evaluate how antigenic shifts relate to dengue epidemic dynamics and disease. This project will provide much needed insight into how pathogens change to escape immunity, and will help guide vaccine efforts.

415
Category:
Stem Cell Biology
Project:

Antiviral mechanisms in Brain Stem Cells in Development and Cancer

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

Virus infection of brain stem cells represents a major global health concern, but also offers treatment possibilities in neurodegenerative diseases and in malignant brain tumours. For example, Zika Virus targets SOX2+ neural progenitors in the developing brain to cause microcephaly in babies born to mothers infected during pregnancy; likewise, it targets SOX2+ glioma stem cells in the most common and lethal malignant brain tumour, glioblastoma (GBM) (https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4135719). Stem cells have been shown to exploit a distinct set of antiviral mechanisms compared to somatic cells (https://doi.org/10.1016/j.cell.2017.11.018), and viral permissivity varies widely between example developing brain and glioblastoma stem cell populations. Understanding and manipulating the cell-intrinsic mechanisms underpinning antiviral resistance in brain stem cells will inform approaches to protect and exploit neural stem cell function and to ablate cancer stem cells in GBM.

This project will seek to understand and modify viral permissivity and antiviral defence mechanisms in developing brain and brain tumours, focusing on stem cell intrinsic pathways. In the first place we will  address the hypothesis that immune selection pressure on glioma stem cells during tumour development results in expansion of a mesenchymal/injury-response cell population (https://www.cell.com/cell/pdf/S0092-8674(21)00351-2.pdf) refractory to virus infection, then proceed to examine underlying mechanisms.

You will be working with human patient-derived and mouse defined mutation glioma cell models, treated with viruses and viral mimetic compounds. You will be assaying transcriptional identity and responses using qPCR and RNA sequencing, immunofluorescence and RNA smFISH, and cytokine secretion using immunoassays. The lab has access to the state-of-the-art Cambridge Stem Cell Institute imaging, FACS, sequencing and bioinformatic facilities, and to additional specialist facilities (e.g. imaging mass cytometry) in the CRUK Cancer Institute next door. We will validate results in mice in vivo and/or slice cultures prepared from  human developing brain and patient brain tumour tissue, models we have established and use routinely in the lab.

414
Category:
Structural Biology
Project:

Structure-function studies of bacterial cell envelope machines involved in pathogenesis

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

Dr. Susan Lea

UK Mentor:

Prof. Ben Berks

University:
Oxford
Project Details:

The bacterial cell envelope comprises the cell wall and either one or two membranes. The cell envelope is of major interest in infection biology because it is the site at which pathogenic bacteria interact with their host organism. In particular, bacterial virulence proteins must be transported across the cell envelope to affect the host.

We aim to understand the molecular mechanisms by which proteins, nucleic acids, and mechanical force are transferred across and along the cell envelope in processes of biomedical importance. The project is to undertake structure-led studies of  the dedicated nanomachines that carry out these processes. The NCI part of the collaboration will involve structural analysis, primarily by cryoEM. The Oxford part of the collaboration will concentrate on complementary mechanistic work using biochemical, genetic, and live cell single molecule imaging methods. Our groups  have collaborated for more than 15 years on projects including the transport of folded proteins across the bacterial inner and outer membranes (Tat protein transport system and Type 9 Secretion System), lipoprotein export, DNA transport during horizontal gene transfer (conjugation and natural competence), and gliding motility.

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.

 

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