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Understanding the role of alpha-actinin in cardiac disease: from molecules to in vivo models


   Institute of Cardiovascular Sciences

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  Dr K Gehmlich, Dr S Loughna, Prof C Denning  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

Birmingham United Kingdom Biochemistry Cell Biology Developmental Biology Genetics Structural Biology

About the Project

In the heart and skeletal muscle, the Z-disc is a crucial structure to anchor thin filaments of the contractile units. Moreover, the Z-disc is recognised as a signalling hub, sensing and responding to changes in the environment. Within the Z-disc, the protein alpha-actinin crosslinks actin filaments [1]. Missense variants in alpha-actinin have been reported to cause cardiac disease (Hypertrophic Cardiomyopathy, [2]). However, the underlying mechanisms of how such mutations cause disease are unknown. This project will investigate the consequences of a cardiac-disease causing alpha-actinin missense variant. It is expected that small changes in the protein structure lead to disturbances of contractility and protein turnover, ultimately compromising heart function. This interdisciplinary project will address the pathogenic mechanisms by exploiting biophysical and structural approaches [3], in combination with the investigations of an induced pluripotent stem cell derived cardiomyocyte model (both in 2D and 3D) and High-resolution Episcopic Microscopy in an in vivo model. Collectively, these studies will identify novel signalling functions of alpha-actinin, define how they are impaired in the presence of the disease-causing variant and will inform development of novel therapies targeting cardiomyopathies.

The PhD position offers the unique opportunity to work in an interdisciplinary research environment. The student will be based at the University of Birmingham, with supervisors and collaborator at the University of Nottingham and the Research Complex Harwell. The project will provide extensive in-depth training in a variety of methods (ranging from structural biology to in vivo work).

Person Specification

Applicants should have a strong background in Cell biology, and ideally a background in in vivo models of cardiac disease. They should have a commitment to research in the cardiovascular field and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject (e.g. Cell Biology, Molecular Cardiology, Genetics). 

How to apply

Informal enquiries should be directed to Katja Gehmlich ([Email Address Removed])

To apply, please download and complete all documentation available at https://more.bham.ac.uk/mrc-aim/phd-opportunities/  

AIM DTP

The MRC Advanced Interdisciplinary Models (AIM) Doctoral Training Partnership (DTP) is a multi-institutional DTP between the Universities of Birmingham, Leicester and Nottingham. You will be based at the institution of the first supervisor. More information about the DTP is here


Funding Notes

This is a fully funded MRC studentship for 4 years. The funding includes a stipend, tuition fees, research/training costs and a budget to help with the cost of purchasing a University laptop.
There are only a limited of places available for international applicants due stipulations set by the funder.

References

[1] Wadmore et al. Int J Mol Sci. 2021 ;22(6):3058.
[2] Girolami et al. Circ Cardiovasc Genet. 2014;7(6):741-50.
[3] Haywood et al. Biochem J. 2016;473(16):2485-93.
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