About the Project
Basement membranes are essential for tissue formation and function in animals. Thin, yet dense structural scaffolds, basement membranes underlie and support all continuous layers of cells and are composed of a complex mix of extracellular matrix proteins. Core components include laminins and type IV collagen, which are highly conserved through evolution. Genetic defects in core basement membrane (BM) components cause a spectrum of rare human diseases, however, recent large genetic studies have shown that variants in BM genes are associated with more prevalent human diseases including diabetic kidney disease, haemorrhagic stroke and cardiovascular disease and affect many organ systems. The significance of these genetic variants is unclear and there are few authentic experimental systems to evaluate the role of genetic variants in BM function. In this interdisciplinary PhD project, we propose an exciting multidisciplinary training programme incorporating basement membrane biology, genomics and human disease. The project will navigate a pipeline of investigation to connect novel genetic variants in basement membrane genes that we have recently identified in the UK 100,000 genomes project to underlying mechanisms of basement membrane regulation. For the mechanistic studies we will use the power of C. elegans to interrogate the effects of genetic variants on basement membrane assembly and regulation using a unique toolkit of fluorescently tagged basement membrane components. These studies will create insights into the effects of genetic variants on basement membrane dynamics. To achieve deep interdisciplinary training the PhD will be conducted at University of Manchester (UK) and Duke University (USA) and jointly supervised by Rachel Lennon (expertise in matrix biology and human disease), Jamie Ellingford (expertise in computational genomics) and David Sherwood (expertise in matrix biology and C. elegans).
Wellcome Centre for Cell-Matrix Research: https://www.wellcome-matrix.org
Manchester Genomics Centre: https://www.mangen.co.uk
Sherwood Lab, Duke University, Durham, USA: https://sites.duke.edu/sherwoodlab/
Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.
Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships
Funding Notes
Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
References
1. Keeley DP, Hastie E, Jayadev R, Kelley LC, Chi Q, Payne SG, Jeger JL, Hoffman BD, Sherwood DR. Comprehensive Endogenous Tagging of Basement Membrane Components Reveals Dynamic Movement within the Matrix Scaffolding. Dev Cell. 2020 Jul 6;54(1):60-74.e7.
2. Rowlands CF, Baralle D, Ellingford JM. Machine Learning Approaches for the Prioritization of Genomic Variants Impacting Pre-mRNA Splicing. Cells. 2019 Nov 26;8(12):1513.
3. Ellingford JM, Horn B, Campbell C, Arno G, Barton S, Tate C, Bhaskar S, Sergouniotis PI, Taylor RL, Carss KJ, Raymond LFL, Michaelides M, Ramsden SC, Webster AR, Black GCM. Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases. J Med Genet. 2018 Feb;55(2):114-121.
4. Randles MJ, Lausecker F, Humphries JD, Byron A, Clark SJ, Miner JH, Zent R, Humphries MJ, Lennon R. Basement membrane ligands initiate distinct signalling networks to direct cell shape. Matrix Biol. 2020 Mar 6.
5. Hale LJ, Howden SE, Phipson B, Lonsdale A, Er P, Ghobrial I, Hosawi S, Wilson S, Lawlor K, Khan S, Oshlack A, Quinlan C, Lennon R, Little MH. Kidney organoid-derived glomeruli provide an approach for personalised podocyte disease modelling at scale. Nat Commun 2018 Dec 4;9(1):5167.
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