Prof C Baldock, Dr Paul Bishop, Dr A Roseman
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Elastic tissues such as eye ligaments, skin and lung contain elastic fibres which are composed of elastin and fibrillin microfibrils. Mutations in elastic fibres disrupt these tissues and result in a wide spectrum of diseases. Collectively they are termed fibrillinopathies as they are typically linked to mutations in fibrillin. However recently, mutations in a family of proteins termed A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats -like (ADAMTS-L) proteins have been found to give rise to the same diseases. The ADAMTSL proteins are multi-domain glycoproteins with a number of thrombospondin repeats and additional ancillary domains. Mutations in ADAMTSL4 give rise to the eye disease ectopia lentis (EL) or dislocated lens, and mutations in ADAMTSL-2 to Geleophysic Dysplasia. ADAMTS-L4 co-localises to fibrillin microfibrils in the eye which is consistent with its role in tethering the lens to the basement membrane. Additionally, an ADAMTSL-4 mutant mouse has disordered fibrillin microfibrils indicating a role for ADAMTS-L4 in microfibril deposition (Collin et al., 2014). However, little is known about the structure of ADAMTSL-4, the interactions it makes or its function in the matrix.
Therefore the aims of this project are:
1) To investigate the interactions between ADAMTSL-4, fibrillin and other elastic fibre proteins using protein interaction assays. The consequence of ADAMTSL-4 EL causing mutations on protein interactions will also be investigated using biochemical and cell-based approaches.
2) To determine the structure of ADAMTSL-4 and an ADAMTSL-4-fibrillin complex using cryoEM and single particle analysis.
3) To define the organisation of ADAMTSL-4 in ocular tissue such as the ciliary zonules using immunohistochemistry and serial blockface SEM imaging.
Combining these interdisciplinary approaches from molecular structure to whole tissue function will allow us to understand the role of ADAMTSL-4 in assembly of ciliary zonules and its function in the eye.
http://www.wellcome-matrix.org/research_groups/clair-baldock.html
http://www.manchester.ac.uk/research/Paul.n.bishop/
http://www.manchester.ac.uk/research/alan.roseman/
Funding Notes
This project is to be funded under the BBSRC Doctoral Training Programme. 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 http://www.dtpstudentships.manchester.ac.uk/
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.
References
Ramsay et al. Structural analysis of X-linked Retinoschisis mutations reveals distinct classes which differentially effect retinoschisin function. Human Molecular Genetics.2016. In Press.
Troilo H, Steer R, Collins RF, Kielty CM, Baldock C. Independent multimerization of Latent TGFβ Binding protein-1 stabilized by cross-linking and enhanced by heparan sulfate. Sci Rep. 2016 6:34347.
Collin et al. Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation. Hum Mol Genet. 2015 24:6958-74.
Keenan et al. Age-dependent changes in heparan sulfate in human Bruch's membrane: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2014 55:5370-9.
Continue with Facebook
