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Elucidating the Mechanism of Muscle Wasting: The Role of Ubiquitin


Project Description

The loss of muscle mass and strength, known as muscle “wasting”, primarily results from excessive protein degradation. There is accumulating evidence to suggest that both the ubiquitin-mediated proteasome and ubiquitin-mediated autophagy systems are major pathways degrade muscle protein (1), but the precise mechanisms remain unclear. Although the ubiquitylation was initially identified as part of the protein degradation signal within the cells, it is now known to be one of the most important reversible post-translational modifications that regulate diverse biological functions. Ubiquitylation is carried out by dedicated ATP dependent machinery consisting of E1 activating, E2 conjugating and E3 ligases, and is reversed by one type of tryptic enzymes called deubiquitylases (DUBs). Further complexity in the system is achieved by the formation of ubiquitylation chains, that exist in multiple chain types or linkages, with each type mediating a unique biological function. As aberrant regulation of ubiquitylation is the main cause of muscle protein degradation and accumulation, modulating the components of ubiquitin signalling is likely to provide strategies for therapeutic interventions.

Objective: The project aims to elucidate the role of ubiquitin signalling in muscle wasting conditions.

Ageing and other aged associated diseases, such as diabete and cancers, are often associated with severe muscle loss. Prof. Lars Holm will provide guidance in developing assays to measure protein breakdown using the state-of-the-art mass spectrometry coupled with isotope labelling. The specific aims of this project are to: (i) investigate a link between aberrant ubiquitin signalling and muscle protein breakdown. (ii) Understand the molecular mechanisms behind the link using molecular, chemical biology and gene editing technology that are developing in the lab (2, 3), and finally (iii) investigate potential drug targets of or other interventions, such as exercise, to prevent muscle wasting. The project is of direct relevance to understanding the pathological mechanisms of how ageing and/or chronic immune disorders lead to muscle atrophy. This research offers the opportunity to investigate and define targets for future drug discovery that will be applicable, not only to ageing but many other common diseases accompanied muscle atrophy. The PhD candidate will have the opportunity to work both clinical and basic laboratories, and develop interdisciplinary skill set including preparation of human/rodent samples, tissue culture, biochemistry, molecular & chemical biology, detailed quantitative proteomics and data analysis.

Funding Notes

This studentship is competition funded by the BBSRC MIBTP scheme: View Website or View Website

Deadline: January 6, 2019

The Midlands Integrative Biosciences Training Partnership (MIBTP) is a BBSRC-funded doctoral training partnership between the universities of Warwick, Birmingham and Leicester. It delivers innovative, world-class research training across the Life Sciences to boost the growing Bioeconomy across the UK.

Enquiries regarding this project should be made to Dr. Yu-Chiang Lai:

References

(1) Cohen S, et al. (2015) Muscle wasting in disease: molecular mechanisms and promising therapies. Nature Reviews Drug Discovery 14(1):58-74.
(2) Pao KC, et al. (2016) Probes of ubiquitin E3 ligases enable systematic dissection of Parkin activation. Nature Chemical Biology 12(5):324-331.
(3) Lai YC, et al. (2015) Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1. EMBO Journal 12;34(22):2840-61.

How good is research at University of Birmingham in Sport and Exercise Sciences, Leisure and Tourism?

FTE Category A staff submitted: 34.40

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