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Role of cellular exosomes in the onset of immune mediated tissue damage

  • Full or part time
  • Application Deadline
    Wednesday, May 15, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Scleroderma (SSc) is an interferon-mediated chronic autoimmune diseases with the highest morbidity and mortality among rheumatologic conditions. This disease is associated with an irreversible tissue and vascular fibrosis. It is not clear what triggers SSc, although a role for autoimmune-driven activation of the Type-I IFN and IL-6 pathways has been suggested. Importantly, fibrosis is not only the major pathological feature of SSc, but is increasingly seen as key for a number of important diseases e.g. cardiovascular disease. Therefore, understanding the key mechanisms by which immune-driven tissue fibrosis causes disease will have important repercussions in major health needs for the ageing population. Additionally, Scleroderma research is fostering major Pharma investment in the coming years.

We have established a unique national cohort of patients that are at risk of progressing to SSc and, as such, manifest the early IFN mediated events that eventually lead to disease. By studying biosamples (skin biopsies and blood samples) from this cohort we have discovered that early activation of immune system is linked to secretion of exosomes. Exosomes are small vesicles that carry proteins and nucleic acids between cells, and which have important roles in intercellular communication. They are increasingly seen as important in a variety of pathological conditions. Separately, we have identified a new pathway that regulate IFN signaling by modulating Deubiquitylase activity. Ubiquitylation of proteins is a post-translational signal that regulates virtually all cellular processes through the precise spatial and temporal control of protein stability, activity or localization. As such, enzymes that perform ubiquitin chain cleavage (called deubiquitylases or DUBs), are frequently mutated in disease and important drug targets in cancer, autoimmune disease and neurodegeneration.

This unique PhD position is perfectly positioned to make the most of the translational lab focused on patient samples (Dr Del Galdo) and basic research labs based on IFN signaling and modulation of ubiquitin-mediated cytokine signaling (Dr McKimmie and Dr Zeqiraj). By understanding the role of exosomes in triggering IFN signalling and the importance of ubiquitylation to regulate this process, you will learn a range of highly specialised cell culture techniques including 3D skin equivalent cultures, ex-vivo skin explants, organotypic fibroblast–endothelial cell co-cultures and matrigel assays to assess the effect of exosomes on fibrosis, immune cells activation and angiogenesis. You will also learn confocal laser scanning and microscopy, Fluorescence activated Cell sorting (FACS) and employ a range of molecular biology techniques including qPCR, western blotting and RNA-seq and Enzyme kinetic measurements and enzyme inhibition.
As such this PhD will provide a number of opportunities to learn key methodologies, gain valuable experience in the translational medicine research environment and discover important new insights into inflammatory and fibrosis-related disease.

Eligibility

You should hold a strong first degree equivalent to at least a UK upper second class honours degree in a relevant biomedical subject. This project would suit a student with a background in cellular and molecular biology.

The Faculty minimum requirements for candidates whose first language is not English are:

• British Council IELTS - score of 6.5 overall, with no element less than 6.0
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

How to Apply

To apply for this scholarship applicants should complete a Faculty Scholarship Application form using the link below https://medicinehealth.leeds.ac.uk/downloads/download/129/faculty_graduate_school_-_application_form and send this alongside a full academic CV, degree certificates and transcripts (or marks so far if still studying) to the Faculty Graduate School

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to by no later than Wednesday 15 May 2019.

If you have already applied for other scholarships using the Faculty Scholarship Application form you do not need to complete this form again. Instead you should email to inform us you would like to be considered for this scholarship project.

Any queries regarding the application process should be directed to

Funding Notes

This scholarship is BRC funded and will attract an annual tax free stipend of £15,009 for up to 3 years, subject to satisfactory progression. It will also cover academic fees at the UK/EU rate.

References

1- M Walden, L Tian, R Ross, UM Sykora, DP Byrne, EL Hesketh, SK Masandi, J Cassel, R George, JR Ault, F El Oualid, K Pawłowski, JM Salvino, PA Eyers, NA Ranson, F Del Galdo, RA Greenberg and E Zeqiraj. Metabolic control of SHMT2 1 oligomerization regulates ubiquitin-dependent cytokine signaling. Nature 2019, (under review).
2- Pingen M, Bryden SR, Pondeville E, Schnettler E, Kohl A, Merits A, Fazakerley JK, Graham GJ, McKimmie CS. Host Inflammatory Response to Mosquito Bites Enhances the Severity of Arbovirus infection. Immunity. 2016 Jun 21;44(6):1455-69
3- Liakouli V, Elies J, El-Sherbiny YM, Scarcia M, Grant G, Abignano G, Derrett-Smith EC, Esteves F, Cipriani P, Emery P, Denton CP, Giacomelli R, Mavria G, Del Galdo F. 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

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