Elucidating the contribution of complement to kidney injury in IgA nephropathy at Imperial College London on FindAPhD.com

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Dr M Pickering No more applications being accepted Funded PhD Project (UK Students Only)

London United Kingdom Human Genetics Immunology Molecular Biology Physiology

About the Project

Stipend: £19,668 (inclusive of London allowance) per annum + Tuition Fees (Home) for 3 years. A consumables budget is also provided.

Fully-funded PhD position in the Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, with an expected start date of 1 March 2023.

The IgA nephropathy research group (Dr Nicholas Medjeral-Thomas and Professor Matthew Pickering) are looking for a PhD candidate who is keen to investigate the mechanisms of kidney damage in IgA nephropathy.

IgA nephropathy (IgAN) is the commonest primary glomerulonephritis worldwide. Lack of effective treatment results in kidney failure and kidney transplant recurrence. Pathogenesis is thought to be due to galactose-deficient IgA1 (gd-IgA1) depositing in glomeruli and triggering inflammation through mesangial cell and complement activation. We have shown that (1) levels of complement regulatory proteins associate with progressive disease (PMID 28673452, PMID 29725647); and (2) using the first large-scale, high-resolution profiling of IgA O- and N- glycosylation in IgAN, decreased sialylation of IgA1 O-glycopeptides associates with kidney function decline (PMID 34127537). This is a key insight since surface sialic acid is known to influence complement activation by enhancing complement regulatory protein binding. Our hypothesis is that IgA1 sialylation influences complement regulatory protein binding to IgA1 and is an important determinant of the degree of complement activation and subsequent kidney injury in IgAN. In this Auchi-funded PhD proposal we will test if decreased IgA1 sialylation triggers 1) complement activation and 2) mesangial cell activation. Elucidating the mechanism of kidney injury in IgAN will lead to new treatment approaches, represents a key unmet need and synergizes with our IgAN clinical expertise and translational work.

The student will work in a multidisciplinary shared research environment in the Centre for Inflammatory Disease (CID) which includes several post-docs, research assistants and clinical research fellows working with Principal Investigators who have diverse research interests and expertise. Please see the CID website for details of our research portfolio. The PhD work will involve in vitro complement assays; cell culture and kidney tissue immunostaining.

Candidates should contact Professor Matthew Pickering ([Email Address Removed]) to discuss their application.

How to Apply:

Applicants are requested to send a full CV (including the names and email addresses of two academic referees), and personal statement detailing why you are interested in the research project (maximum 1 side A4, font size 12 Arial) to Edward Wallace ([Email Address Removed]). The successful candidate will be asked to complete an electronic application form at Imperial College London so their qualifications can be reviewed by College Registry.

Funding Notes

This PhD position includes a tax-free stipend and Home fees and consumables for 3 years. Qualification for Home fees is only available to UK citizens or those who have been resident in the UK for a period of 3 years or more. More detail is provided in UKCISA's guide: https://ukcisa.org.uk/uploads/files/1/england_he_who_pays__home_fees_public_version6_21.12.21.pdf. Non-Home students are welcome to apply, but should be able to demonstrate adequate financial support to cover the difference between the Home fee and the Non-Home fee. Applicants are also required to meet Imperial College’s English language requirements. Please see the following link: https://www.imperial.ac.uk/study/pg/apply/requirements/english/

References

1. Medjeral-Thomas NR, Cook HT, Pickering MC. Complement activation in IgA nephropathy. Semin Immunopathol. 2021;43(5):679-690. PMID 34379175. (https://pubmed.ncbi.nlm.nih.gov/34379175/)
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2. Medjeral-Thomas NR, Lomax-Browne HJ, Beckwith H, Willicombe M, McLean AG, Brookes P, Pusey CD, Falchi M, Cook HT, Pickering MC. Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy. Kidney Int. 2017. PMID 28673452. (https://pubmed.ncbi.nlm.nih.gov/28673452/)
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3. Medjeral-Thomas NR, Troldborg A, Constantinou N, Lomax-Browne HJ, Hansen AG, Willicombe M, Pusey CD, Cook HT, Thiel S, Pickering MC. Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin-Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H-Related Protein-5 (FHR5) Deposition. Kidney Int Rep. 2018;3(2):426-38. PMID 29725647. (https://pubmed.ncbi.nlm.nih.gov/29725647/)
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4. Dotz V, Visconti A, Lomax-Browne HJ, Clerc F, Hipgrave Ederveen AL, Medjeral-Thomas NR, Cook HT, Pickering MC, Whurer M, Falchi M. O- and N-Glycosylation of Serum Immunoglobulin A is Associated with IgA Nephropathy and Glomerular Function. J Am Soc Nephrol. 2021;32:2455-2465. PMID 34127537. (https://pubmed.ncbi.nlm.nih.gov/34127537/)
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5. Kim MJ, McDaid JP, McAdoo SP, Barratt J, Molyneux K, Masuda ES, Pusey CD, Tam FW. Spleen tyrosine kinase is important in the production of proinflammatory cytokines and cell proliferation in human mesangial cells following stimulation with IgA1 isolated from IgA nephropathy patients. J Immunol. 2012;189(7):3751-8. PMID 22956578. (https://pubmed.ncbi.nlm.nih.gov/22956578/)
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6. Liu P, Lassen E, Nair V, Berthier CC, Suguro M, Sihlbom C, Kretzler M, Betsholtz C, Haraldsson B, Ju W, et al. Transcriptomic and Proteomic Profiling Provides Insight into Mesangial Cell Function in IgA Nephropathy. J Am Soc Nephrol. 2017;28(10):2961-72. PMID 28646076. (https://pubmed.ncbi.nlm.nih.gov/28646076/)