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MRC DiMeN Doctoral Training Partnership: Characterisation of OX40L reverse signalling and its role in the pathogenesis of fibrosis


Project Description

Scleroderma (SSc) is a prototypic fibrotic disease, in which an autoimmune mediated injury leads to loss of tissue function through accumulation of extracellular matrix in the skin and internal organs. Activated fibroblasts in SSc are known to act as antigen presenting cells (APCs) to initiate or perpetuate autoimmunity and tissue damage. However, the effects of activated immune cells on APCs (“reverse signalling”), and its contribution to fibrosis, is just starting to be appreciated. OX40L, a transmembrane ligand capable of activating a co-stimulatory receptor in T cells, is highly expressed in skin fibroblasts from SSc patients. While the effects of this expression on T cell activation are well described, the biological effects of OX40L engagement in the presenting fibroblast are unknown. With a current grant from our industry partner, we investigated transcriptional changes after OX40L activation in SSc fibroblasts by RNA-seq.

This PhD project will investigate the mechanisms and effects of OX40L resverse signalling through three specific aims:
1- Discover the transcriptional programmes activated in SSc fibroblasts upon stimulation with recombinant OX40L receptor.
2- Identify intracellular OX40L-interacting proteins and delineate the signalling pathway(s) activated in fibroblasts.
3- Determine the effect of OX40L activation on Sonic Hedgehog (Shh), Wnt, and Transforming Growth Factor TGF signalling in SSc.

Experimental approach: Cell culture, RNA-seq analysis, overexpression and silencing (siRNA) of selected genes, identification of interacting proteins by immunoprecipitation and mass spectrometry, genome editing by CRISPR-Cas9, functional assay to study Shh, Wnt and TGF signalling, qRT-PCR, western blot.

This project will be undertaken in partnership with a therapeutic antibody company based in Cambridge, that will provide expertise in the field of OX40, training in the workplace and additional consumables and salary support for the successful candidate.

Primary supervisor:
Dr. Natalia Riobo-Del Galdo
https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/130/dr-natalia-riobo-del-galdo

Co-supervisor:
Dr. Francesco Del Galdo
https://medhealth.leeds.ac.uk/profile/760/662/francesco_del_galdo

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.

Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

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