(BBSRC DTP) Pathways to protein aggregation during cellular responses to stress

Misfolded proteins are usually refolded to their functional conformations or degraded by quality control mechanisms. When misfolded proteins evade quality control, they form aggregates that are sequestered to specific sites within cells. Although aggregation is a well-studied phenomenon and many key players are known, it remains unclear exactly how different growth and stress conditions cause protein aggregation and the degree of stress specificity in the response to aggregate formation is unknown. In principle, all proteins can form aggregates, particularly if they become misfolded or denatured, exposing hydrophobic surfaces which have a greater propensity to associate and aggregate. We know very little about the kinetics of protein aggregation, or the defence systems which mitigate the toxic consequences of aggregate formation. Our recent data have implicated oxidative stress in the formation of large amorphous protein aggregates using a yeast model system. We will build on this preliminary data to define the role of misfolded protein localization to defined stress-induced protein deposits as a defence system that protects against protein oxidative damage. This will include elucidating how misfolded proteins are sequestered to defined intracellular deposition sites following oxidant exposure. We will test the hypothesis, supported by recent literature and our own preliminary data, that protein aggregates and the attendant mechanisms to deal with it are stress-specific – and therefore likely involve both common and specific proteins in different amounts and combinations. We aim to characterise these processes at the molecular level, using a combined proteomics and cell biological approach. We will also track how generic and stress-specific aggregating proteins interface with protein quality control mechanisms. This research will be relevant to biotechnology where protein misfolding and aggregation can be detrimental for the production of biopharmaceuticals and other high-value recombinant proteins.

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships