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Dissecting the epigenetic and transcriptional regulators of persistent pro-fibrotic growth in keloid scars


   William Harvey Research Institute

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  Dr E Rognoni, Prof M Philpott, Dr T Shaw, Prof E O'Toole  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

This is an exciting opportunity for a 3-year British Skin Foundation 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) in collaboration with King’s College London. Applications are invited from highly motivated graduates with a BSc (First or Upper Second) or MSc (Distinction or Merit) from biological or related sciences. Previous research experience in ATAC/RNA-seq analysis, molecular biology techniques and cell culture 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:

Skin fibrosis is a pathological scarring process affecting more than 100-million people every year that can manifest in association with systemic diseases (e.g. scleroderma) or locally following chronic tissue injuries resulting in hypertrophic or keloid scars [1,2]. So far there are no specific treatments to halt or revert fibrosis, emphasising the great unmet clinical need. Although fibroblasts residing in the connective tissue have been identified as the major source of fibrosis, the cell intrinsic molecular mechanisms maintaining their pathological features long-term are largely unknown. Our project hypothesis is that pathologically fibrotic fibroblasts such as in keloid scars are epigenetically locked in an activated state, and that manipulation of this aspect of diseased cells has anti-fibrotic therapeutic potential. The aim of this project is to define and ultimately block the chromatin and transcriptional changes that accompany the persistent fibrotic cellular phenotype in disease and explore their therapeutic potential.

Using a physiologically relevant 3D-culture model we will screen skin fibroblasts from normal, healthy scar and diseased keloid tissue for intrinsically maintained pro-fibrotic phenotypes (Objective-1). Our preliminary data show that repopulating normal skin dermal scaffolds with healthy human fibroblasts results in cells quiescing (mimicking physiological conditions) but diseased cells from keloid scars persist in their fibrotic state [3]. By comparing healthy and pathological fibroblasts we will dissect the underlying epigenetic and transcriptional regulators using a state-of-the-art sequencing approach, combining ATAC-seq and RNA-seq (Objective-2). Comprehensive bioinformatics analysis will reveal potential intrinsic regulators of persistent pro-fibrotic behaviour which will be validated in human tissue sections. We will then test if pharmacological or genetic inhibition of identified candidates in our 3D-culture model can block fibrosis and thus represent promising targets for the treatment of fibrotic skin diseases (Objective-3).

Upon completion, this PhD studentship will provide essential new knowledge on the transcriptional and epigenetic changes inhibiting resolution of pathological fibroblasts which will support the development of new fibroblast-targeted therapies for keloids and potentially other connective tissue disorders [2,4].

 

Environment and PhD 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 the 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 PhD student will benefit from a state-of-the-art infrastructure including superb imaging, flow cytometry, tissue culture and histology core facilities, with dedicated support staff at QMUL and KCL. The student will be supervised primarily by the first supervisor, but with regular input and support from the second and third supervisors. Both host laboratories are well staffed with both research (PDRAs) and core technical staff who will provide expertise and local training for the PhD student. As well as learning key cell biology techniques, the student will receive bioinformatics training in RNA-seq/ATAC-seq analysis from the Genomics Core facility at QMUL. Students will receive support to attend international and national conferences, e.g., BAD and ESDR annual meeting.

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 Notes:

The 3-year PhD studentship and project consumables are funded by British Skin Foundation with a tax-free stipend including London weighting of £17,609 (in 2021/22). Home 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/

Interviews are planned in the last week of February 2022. The studentship is available immediately and candidates should be available to start in April 2022 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. 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. 

To Apply now for Semester 3 please click here


References

1. Distler JHW, Györfi AH, Ramanujam M, Whitfield ML, Königshoff M, Lafyatis R. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol.; 2019;15:705–30.
2. Shaw TJ, Rognoni E. Dissecting Fibroblast Heterogeneity in Health and Fibrotic Disease. Curr Rheumatol Rep. Current Rheumatology Reports; 2020; 22:33.
3. Rognoni E, Pisco AO, Hiratsuka T, Sipilä KH, Belmonte JM, Mobasseri SA, Philippeos C, Dilão R, Watt FM. Fibroblast state switching orchestrates dermal maturation and wound healing. Mol Syst Biol. 2018, 14(8), e8174.
4. Kirk, T.; Ahmed, A.; Rognoni, E. Fibroblast Memory in Development, Homeostasis and Disease. Cells 2021, 10, 2840
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