About the Project
We offer an exciting opportunity to investigate the molecular basis underlying tissue fibrosis, at the epigenetic, molecular and cellular level. Tissue fibrosis is the result of regeneration gone bad and it impairs the function of the tissues affected. For example, skin fibrosis is accompanied by hardening of the skin limiting movement and by loss of hair, while fibrosis of the heart after myocardial infarction limits its contractility and seriously impairs the function of the heart as a pump. A characteristic of fibrosis is the activation of tissue resident fibroblasts to secrete large amounts of collagen to the extracellular matrix that change the microenvironment for the tissue-specific cell types.
This PhD opportunity builds onto a strong collaboration between a clinician scientist and a basic scientist to study the molecular basis of changes in signal transduction that occurs in fibroblasts when they undergo activation. For this study, we use Scleroderma as a model of fibrosis, an autoimmune disorder of unknown aetiology that results in widespread fibroblast activation, commonly diagnosed in the skin, but in severe cases extended to internal organs like lungs and heart. We have found key differences in signalling of the morphogens Shh, Wnt, and TGF- in fibroblasts isolated from patients or healthy controls, and a striking distinctive shortening of the primary cilium in the diseased cells. The primary cilium is like a cellular antenna where several key receptors localise, and subtle changes in its morphology have been known to cause a large range of defects and disorders. In this PhD project, you will investigate if the morphological change in the primary cilium of fibrotic fibroblasts is the cause of the defective response to important signalling molecules that maintain the normal anatomy and function of the skin. You will also study if the short cilia are the result of epigenetic changes that persist in the cell population or if they are easily reversible and amenable to therapeutic interventions.
The PhD will be conducted partly in the Faculty of Biological Sciences in the main campus of the University of Leeds, working with Dr. Riobo-Del Galdo’s group in signal transduction, protein purification, molecular biology, high resolution imaging and biochemical assays. In Dr. Del Galdo’s lab located in the St. James’ University Hospital campus, you will get training in handling of patient biopsies, isolation of primary cells, and engineering of in vitro multi-layered “skin equivalents” to investigate the effect of the primary cilium and morphogen signalling on epidermal growth and angiogenesis assays. In both groups, you will receive training in statistical analysis and presentation of your data and will be encouraged to communicate your findings to the supervisors’ groups, at the School level, and in national and international scientific conferences.
Please visit your supervisor’s web pages for more information of their interests and for the most up-to-date publications.
Dr. Natalia Riobo-Del Galdo
https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/130/dr-natalia-riobo-del-galdo
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
Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.
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: https://goo.gl/8YfJf8
Good luck!
References
Gillespie J et al. Transforming Growth Factor β Activation Primes Canonical Wnt Signaling Through Down-Regulation of Axin-2. Arthritis Rheumatol. 2018 Jun;70(6):932-942.
Liakouli V et al. Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor. Ann Rheum Dis. 2018 Mar;77(3):431-440.
Ho Wei L et al. Activation of the Gi protein-RHOA axis by non-canonical Hedgehog signaling is independent of primary cilia. PLoS One. 2018 Aug 27;13(8):e0203170.
Brennan-Crispi D et al. Overexpression of Desmoglein 2 in a mouse model of Gorlin syndrome enhances spontaneous basal cell carcinoma formation through STAT3-mediated Gli1 expression. J Invest Dermatol. 2018 Oct 3. pii: S0022-202X(18)32647-2.
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