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How does fibrillin regulate TGFβ latency and activation?


Project Description

Fibrillin microfibrils are an essential component of our connective tissues and they give tissues such as lung, skin and blood vessels their elasticity. In addition, fibrillin is essential for the latency and storage of TGFβ family growth factors within the matrix, providing a tissue store which is critical for normal development and tissue homeostasis. When fibrillin is disrupted or decreased, as seen in Marfan syndrome and other genetic diseases caused by fibrillin mutations, there is an increase in active TGFβ. This paradox is not currently understood but indicates that in the absence of fibrillin, TGFβ can be more readily activated. Therefore, we wish to understand the role of fibrillin in controlling the bioavailability of TGFβ.

This studentship will address the hypothesis that proTGFβ is stabilised when bound to fibrillin making it more resistant to integrin activation to explain the regulatory control fibrillin has on TGFβ activation. The studentship will focus on this fundamentally important issue and will provide the student with training in a range of state-of-the-art methodologies; these include mammalian cell culture, glycoprotein purification and characterization, biomolecular interaction analyses and advanced imaging technologies using cryo-electron microscopy and image analysis.

This work is a vital first step in understanding the extracellular regulation of TGFβ signalling by the matrix. It is anticipated that greater understanding of this process will lead to better understanding of how TGFβ is dysregulated in disease and may ultimately lead to the development of novel agents to treat diseases associated with dysregulated TGFβ signalling e.g. cancer.

The studentship will provide the student with training in a range of state-of-the-art methodologies; these include mammalian cell culture, glycoprotein purification and characterization, biomolecular interaction analyses and advanced imaging technologies using cryo-electron microscopy and image analysis.

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 http://www.internationalphd.manchester.ac.uk.

Funding Notes

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

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).

Informal enquiries may be made directly to the primary supervisor.

References

Thomson J, Singh M, Eckersley A, Cain SA, Sherratt MJ, Baldock C. Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors. Semin Cell Dev Biol (2018) doi: 10.1016/j.semcdb.2018.07.016.
A.F. Godwin, T. Starborg, M.J. Sherratt, A.M. Roseman, C. Baldock. Multiscale Imaging Reveals the Hierarchical Organisation of Fibrillin Microfibrils. In press J Mol Biol. (2018).
H. Troilo, R. Steer, R.F. Collins, C.M. Kielty, C. Baldock. Structural analysis of LTBP1 reveals independent multimerization stabilized by cross-linking and enhanced by heparan sulfate. (2016) Sci Rep. 6:34347.
A.P. Wohl, H. Troilo, R.F. Collins, C. Baldock, G. Sengle. Extracellular regulation of BMP activity by fibrillin-1. (2016) J Biol Chem 291:12732-46.

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