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(BBSRC DTP) Consequences of ageing on protein homeostasis and structure


   Faculty of Biology, Medicine and Health

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  Dr Joe Swift, Prof Simon Hubbard, Dr Argyris Politis  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The World Health Organisation estimates that by 2050, there will be two billion people aged 60 and above. Despite this remarkable progress in extending human life, health issues specific to the ageing body can severely limit the quality of life and well-being of the elderly. Cellular senescence – the cessation of cellular division – is a recognised ‘hallmark’ of the ageing process. Senescent cells accumulate in our tissues during ageing, where they can affect regulation of metabolism, the immune system and the extracellular matrix. Furthermore, our laboratories have recently established that senescent cells are less able to respond to environmental cues than healthy cells, due to a loss of the protein machinery required for protein homeostasis. This means that when faced with stressful conditions (such as heat, or mechanical load), senescent cells are less able to respond appropriately by making new proteins, or by removing proteins that are unneeded or damaged. In addition to expressing the required quantities of protein, cells must also ensure that those proteins are folded into functional states, subjected to the right chemical modifications, and transported to where they are needed. This project will seek to understand the consequences of senescence (and senescence-associated loss of cellular responsiveness) on the post-translational processing required for protein function. To achieve this, proliferating and senescent cells will be subjected to thermal stress, and their responses characterised using a toolbox of mass spectrometry (MS) methods. Quantitative ‘bottom-up’ MS analysis – which is based on detection of protein fragments following enzymatic digestion, and can deliver parallel analysis of thousands of proteins – will be complemented by more focused structural-MS techniques, capable of a greater depth of analysis, but on fewer proteins. Hydrogen-deuterium exchange (HDX) MS analysis, for example, will be used to ascertain which regions of a target protein are surface exposed, versus regions that are sequestered within the folded structure. Finally, bioinformatic methods will be developed to map together evidence from -omic and structural methods, thus constructing a holistic picture of the ageing stress response. Overall, this project will offer opportunities for diverse, multidisciplinary training and promises to contribute to an understanding of the ageing process and how interventions to age-associated pathology might be targeted. 

Eligibility 

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.  

Before you Apply 

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.  

How To Apply 

To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/  

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]  

Equality, Diversity and Inclusion  

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/ 


Funding Notes

Studentship funding is for 4 years. This scheme is open to both the UK and international applicants. We are only able to offer a limited number of studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell (2013) 153 (6), 1194-1217.
Hipp MS, Kasturi P, Hartl FU. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol (2019) 20, 1-15.
Llewellyn J, Mallikarjun V, Appleton E, Osipova M, Gilbert HTJ, Richardson SM, Hubbard SJ, Swift J. Senescence inhibits the chaperone response to thermal stress. BioRxiv (2021) https://doi.org/10.1101/2021.06.15.448532
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