Decoding muscle wasting

Description

We are all familiar with the rapid and dramatic weight loss that accompanies the decline of a seriously ill loved-one or friend. This “wasting” is not a disease in itself, but a consequence of disease. By preventing it, there is little argument that patient well-being would be improved.

Virtually all body proteins are continually made and destroyed and this is maintained is through the process of protein homeostasis, or proteostasis. Normally, proteins are synthesised and degraded in an equilibrium ensuring constant protein levels. Changes in abundance are mediated by adjusting the rates of synthesis and/or degradation, that is, the rate of protein “turnover”. But in wasting, the balance is lost, and we degrade more proteins than we make.

You will join a strong team of multidisciplinary researchers investigating the fundamental cellular process of proteostasis and investigate the changes in protein expression, turnover and activity that underlie the development and progression of the muscle wasting synonymous with chronic illness, in this case the cachexia induced by cancer.

Within cells, the two main protein degradation pathways with broad selectivity are lysosome-mediated autophagy and the ubiquitin proteasome system. In animal models of skeletal muscle wasting, there are increased levels of ubiquitinated proteins, suggesting an increased formation of ubiquitinated proteins that are then targeted to the proteasome for degradation. Expression of several enzymes in the ubiquitin conjugation pathway are induced in wasted muscle but their genetic inactivation only partially protects from muscle wasting, suggesting that other mechanisms may be involved. Opposing the enzymes involved in ubiquitin conjugation are the deubiquitinating enzymes. The potential role of these in muscle wasting is largely unexplored.

Through a collaboration with Almac Discovery, the effect of a novel inhibitor of a deubiquitinating enzyme implicated in proteostasis, USP19, will be tested in both in vitro and in vivo model systems.

You will receive training in classical cell culture, molecular biology, genetics and biochemistry as well as multidisciplinary systems biology-based research methodologies including quantitative high-resolution liquid chromatography tandem mass spectrometry, multi-omics data integration and computational bioinformatics. In addition, you will engage with a team incorporating chemists, structural biologists, bioinformaticians and pharmacologists within industry and receive mentorship in the commercial aspects of bioscience research.

This is an exciting project employing cutting-edge approaches and technology to reveal important insights into proteostasis, a fundamental cellular process of great importance.

Informal enquiries may be made to 

HOW TO APPLY

Applications should be made by emailing  with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.

In addition to the CV and covering letter, please email a completed copy of the Newcastle-Liverpool-Durham (NLD) BBSRC DTP Studentship Application Details Form (Word document) to , noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Availability

Open to students worldwide

Funding information

Funded studentship

CASE studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Supervisors

References

1.Turnover of the human proteome: determination of protein intracellular stability by dynamic SILAC. (2009) J Proteome Res. 8, 104.
2.Protein turnover measurement using selected reaction monitoring-mass spectrometry (SRM-MS). (2016) Phil. Trans. R. Soc. A. 28, 374(2079).
4.Proteome Dynamics: Tissue Variation in the Kinetics of Proteostasis in Intact Animals. (2016) Mol Cell Proteomics. 15, 1204.
5.Molecular basis of USP7 inhibition by selective small-molecule inhibitors. (2017) Nature. 26;550(7677):481-486.
6.USP30 sets a trigger threshold for PINK1–PARKIN amplification of mitochondrial ubiquitylation. (2020) Life Sci Alliance. 3(8).
7.The deubiquitylase USP9X controls ribosomal stalling (2020) bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.042291.