This is an exciting opportunity for a 4-year Barts Charity funded PhD studentship within the world-renowned William Harvey Research Institute at Barts and The London Medical School and Dentistry (SMD) at Queen Mary University of London (QMUL). Applications are invited from highly motivated graduates with a BSc (First or Upper Second) or MSc (Distinction or Merit) from biological or related science. Previous research experience in single cell RNA-seq analysis, molecular biology techniques and animal work would be an advantage. Applicants should have a high level of proficiency with computer software related to laboratory research, data presentation and statistical evaluation, as well as the ability to organise a varied workload and to work within a team.
Project background:
Fibrosis describes an excessive accumulation of connective tissue in chronic tissue injury. This pathological scarring results in a progressive destruction of the tissue architecture and organ function and can occur in almost every organ. Organ fibrosis is estimated to contribute to over one third of natural deaths worldwide and represents one of today’s major health-care burdens. Specific therapies to prevent, halt or even reverse existing tissue fibrosis are not yet available in any organ [1]. Fibroblasts, the largest cell population in connective tissues, are best known for their role in depositing and maintaining extracellular matrix. Recent advances in single cell transcriptomics and lineage tracing analysis have uncovered an unexpected functional fibroblast heterogeneity in multiple tissues [2]. In skin we and others have shown that during development multipotent fibroblasts differentiate into several subpopulations (lineages) with distinct functions and spatial organisation that give rise to the dermal sublayers including the papillary and reticular dermis [3]. In homeostasis most fibroblasts quiesce but are rapidly “activated” during tissue repair. While this is usually transient, it becomes persistent/irreversible in fibrotic diseases. How pro-fibrotic phenotypes in fibroblasts are maintained long-term and which specific subpopulations are promoting the fibrotic response in skin fibrosis, is largely unknown and will be the focus of this PhD studentship.
Project objectives:
We will dissect the fibroblast heterogeneity in skin fibrosis and unravel the molecular and cellular mechanisms promoting and maintaining pro-fibrotic fibroblast behaviour. Using a state-of-the art single cell RNA-seq approach in Objective-1 we will explore the change in fibroblast behaviour and diversity in a mouse skin fibrosis model that recapitulates the human disease. In Objective-2 we will compare the generated results of normal and diseased skin with recently published datasets of healthy wound fibroblasts. This comparison will reveal the cellular and molecular factors responsible for the persist pathological fibroblast behaviour in fibrosis, which we will further elucidate in physiologically relevant 2D/3D fibroblast culture platforms in Objective-3. Identified candidates will be genetically (shRNA/overexpression) or chemically (inhibitors/activators) manipulated in healthy and diseased fibroblasts and functionally analysed with a diverse range of cell biology techniques/assays. In collaboration with clinicians, identified master regulators will be validated in human tissue and considered for therapeutic applications.
Upon completion, we will make an important contribution to our understanding of the fibroblast heterogeneity in skin fibrosis and core signalling networks halting pro-fibrotic fibroblasts in an activated state. Our goal is to identify the major fibroblast populations in skin fibrosis and develop strategies to specifically target or manipulate these fibroblasts for therapeutic applications in the future.
Environment and Training:
QMUL has an outstanding reputation for its research including in the field of skin biology and the training of PhD students. Located in the centre of London it integrates several world-leading research centres including the William Harvey Research Institute and Centre for Cell Biology and Cutaneous Research at the Blizard Institute creating a strong multidisciplinary research environment delivering both high quality basic and translational research. The student will benefit from a state-of-the-art research infrastructure including an excellent animal unit and superb imaging, flow cytometry, tissue culture and histology core facilities, with dedicated support staff. As well as learning key cell biology techniques, the student will receive bioinformatics training in single RNA-seq analysis from our experienced collaborator Dr. Sascha Ott (University of Warwick) and the Genomics Core facility at QMUL. In addition, the student will complete an animal handling course and obtain their Home Office Personal License (PIL).
For more information please contact Dr Emanuel Rognoni ([Email Address Removed]) and visit the QMUL website (https://www.qmul.ac.uk/whri/people/academic-staff/items/rognoniemanuel.html).
Funding & application details:
The 4-year PhD studentship and project consumables are funded by Barts Charity with a tax-free stipend including London weighting of £24,278 (in 2019/20). Home/EU tuition fees will be paid by the funding body. All students must meet English language entry requirements, more information can be found here: https://www.qmul.ac.uk/international-students/englishlanguagerequirements/postgraduateresearch/
Applications should be sent directly to QMUL admissions via this link:
https://www.qmul.ac.uk/postgraduate/research/subjects/medicine-william-harvey-research-institute.html "
Interviews are planned in the first week of March 2021. The studentship is available immediately and candidates should be available to start in April 2021 or shortly thereafter.
Your application should include a Curriculum Vitae (CV) and a one-side A4 statement of purpose, setting out your previous academic or other experience relevant to the proposed research; why you wish to undertake this research at QMUL; your previous research or professional training and what further training you think you will need to complete a PhD; and what ethical issues you will need to consider in undertaking this research. In addition, two referees should be named at the end of the statement. At least one reference must be from an academic referee who is in a position to comment on the standard of your academic work and suitability for postgraduate level study. Where appropriate, a second referee can provide comment on your professional experience.
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