The role of collagen VI in the skeletal muscle stem cell niche using combined imaging approaches including CryoEM

University of Manchester

Faculty of Biology, Medicine and Health

Project Description

Collagen VI is a unique member of the collagen superfamily which assembles to form beaded microfibrils which associate with basement membranes to anchor the membrane to the extracellular matrix in many human tissues. Collagen VI is essential in maintaining skeletal muscle which is highlighted by the linkage of collagen VI mutations to muscular dystrophy. Collagen VI is found surrounding satellite cells (skeletal muscle stem cells) to maintain their environment. We have recently analysed the 3D structure of collagen VI which will allow us to understand the molecular details that underpin its essential function in maintaining the satellite cell niche. Important questions include: what are the key interacting matrix proteins that bind to collagen VI? What are the essential regions of collagen VI that underpin these interactions? And what interactions does collagen VI facilitate between satellite cells and the surrounding matrix?

To answer these questions, this project aims to determine the interactions between collagen VI and other matrix proteins, that underpin its function in basement membranes. Protein interaction will be used to determine whether interaction with collagen VI enhances secondary interactions to facilitate assembly. Cryo-Electron Microscopy will be utilised to analyse the 3D structure of collagen VI complexes to highlight regions important for collagen VI function which can be correlated with mutation data. To understand the role collagen VI plays in the skeletal muscle stem cell niche, muscle tissue will be imaged using electron tomography and serial blockface SEM to generate 3D reconstructions, these approaches will be supported by immunolocalization to further validate the findings of the protein interaction analyses. Together these combined approaches will enable us to determine the interactions of collagen VI with other matrix proteins that underpin its essential function in basement membranes and will highlight how these may be disrupted when collagen VI is mutated.

Funding Information

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Eligibility Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in Biochemistry or a related area / subject. Candidates with experience in electron microscopy or with an interest in cryoEM are encouraged to apply.

Application Process

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (Apply now). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Biochemistry.

Supplementary Information

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit here.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

A.R. Godwin, T. Starborg, M.J. Sherratt, A.M. Roseman, C. Baldock. Defining the hierarchical organisation of collagen VI microfibrils at nanometre to micrometre length scales. (2017) Acta Biomater. 52:21-32.

E.J. Mularczyk, M. Singh, A.R.F. Godwin, F. Galli, N. Humphreys, A.D. Adamson, A. Mironov, S.A. Cain, G. Sengle, R.P. Boot-Handford, G. Cossu, C.M. Kielty, C. Baldock. ADAMTS10-mediated tissue disruption in Weill-Marchesani Syndrome. Human Molecular Genetics (2018) 27:3675-3687.

A.F. Godwin, T. Starborg, M.J. Sherratt, A.M. Roseman, C. Baldock. Multiscale Imaging Reveals the Hierarchical Organisation of Fibrillin Microfibrils. Journal of Molecular Biology (2018) 430:4142-4155.

To apply for this PhD, please use the following application link: https://www.bmh.manchester.ac.uk/study/research/apply/

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