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(BBSRC DTP) The role of collagen VI in the skeletal muscle stem cell niche using combined imaging approaches including Cryo-EM


Project Description

Collagen VI is a unique member of the collagen superfamily which has a short collagenous region but arrays of globular domains and assembles to form beaded microfibrils. These microfibrils associate with basement membranes in most human tissues to anchor the basement membrane to the surrounding extracellular matrix. Collagen VI has an essential function 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 determined the 3D structure of collagen VI microfibrils using cryo-EM which is now allowing us to understand the role of different regions of collagen VI in its assembly but the molecular details that underpin its essential function in maintaining the satellite cell niche are unknown. 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 essential function in basement membranes. Protein interaction assays using the Bio-Layer Interferometry (Octet system) will be used to determine whether interaction with collagen VI enhances secondary interactions to facilitate assembly. CryoEM will then 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. The Baldock lab is in the Wellcome Centre for Cell-Matrix Research and this project provides an excellent opportunity to be trained in a range of imaging and biomolecular analysis techniques.

http://www.wellcome-matrix.org/research_groups/clair-baldock.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

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

1. M. Cescon, F. Gattazzo, P. Chen, P. Bonaldo. Collagen VI at a glance. (2015) J Cell Sci. 128:3525-31.
2. Urciuolo A, Valeria Morbidoni A, Gattazzo F, Quarta M, Grumati P, Molon S, Montemurro F,Tedesco FS, Cossu G, Vozzi T, Rando TA, Bonaldo P. (2013). Collagen VI is a key component of satellite cell niche. Nature Comm. 4:1964.
3. 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.
4. Frank J. Advances in the field of single-particle cryo-electron microscopy over the last decade. Nat Protoc (2017) 12:209-212.

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