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(MRC DTP) Role of stress granules in stress resistance and ageing: a double-edged sword


Project Description

How cells cope with a stressful environment is a fundamental question in biology that significantly impacts human health. Appropriate stress responses underpin resistance to injury and disease thus promoting healthy life. A universal and essential response to stress in eukaryotes is the formation of stress granules (SG) in the cytoplasm of cells. These granules are a prominent example of a new paradigm for understanding cell biology: that cellular processes can be regulated by the dynamic compartmentalisation of biomolecules into membraneless organelles driven by liquid-liquid phase separation. SGs harbour multiple RNA binding proteins complexed with RNAs and are initiated by a general inhibition of translation initiation in response to stress. However, they are stress-selective: they capture many protein synthesis components, but do not retain mRNAs whose translation are pivotal to the stress response in question. The granules also provide dynamic outcomes: the stored mRNAs are released for future translation should conditions improve, or else are directed to alternative fates such as degradation. SGs act as a hub to coordinate intracellular signalling with translational shutdown and mRNA fate. Whilst usually protective, SGs can seed toxic protein aggregates and are implicated in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Furthermore, impaired dynamics of SG assembly is a feature of cancer cells and of ageing. Hence SGs shape cellular and organismal survival, yet important questions about their function abound. The project will utilise cultured cells and the model organism C. elegans to enhance our understanding of the double-edged role that SGs play in promoting stress resistance but also contributing to disease and ageing phenotypes.

https://www.research.manchester.ac.uk/portal/alan.j.whitmarsh.html
https://www.research.manchester.ac.uk/portal/mark.p.ashe.html
https://www.research.manchester.ac.uk/portal/gino.poulin.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Protter & Parker, Trends Cell Biol 26:668-79, Shin & Brangwynne, Science 357:eaaf4382, Lechler et al., Cell Rep 18:454-67, Sfakianos et al., Cell Death Diff 25:1766-80.

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