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Identifying the mechanisms of persistent mTORC1 in senescence

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  • Full or part time
    Dr B Carroll
  • Application Deadline
    No more applications being accepted

Project Description

The proper control of cell growth is essential to maintain tissue and organismal homeostasis. Too much growth, or too little can have drastic effects on human health and dysregulation of the pathways that control growth are widely implicated in driving ageing and age-related disease.

One of the key determinants regulating cell growth is the mammalian target of rapamycin complex 1 (mTORC1) which is able to sense the availability of mitogens such as amino acids and growth factors and detect stress signals. Active mTORC1 drives growth via synthesis of new proteins, lipids and nucleotides and inhibits the catabolic process of autophagy. The dynamic regulation of mTORC1 activity allows cells to rapidly respond to changes in the environment, to promote an anabolic metabolism in favourable conditions while switching on catabolic, pro-survival mechanisms when they are not. Thus, mTORC1 dictates how much and when a cell will grow.

We and others have shown that mTORC1 is dysregulated in a process called cellular senescence, a potent tumour suppressor mechanism and established driver of ageing. This leads to increased cell size and contributes to the production of pro-inflammatory factors. Inhibition of mTORC1 can suppress senescence and is one of the most robust interventions ever identified to improve healthy lifespan of yeast, worms, flies and mice. Despite its important role in senescence, the mechanisms via which mTORC1 is dysregulated are not well understood.

This PhD project will employ molecular and cell biology techniques including protein biochemistry, high-resolution microscopy and quantitative proteomics to investigate the molecular mechanisms controlling mTORC1 in senescence. The applicant will have the opportunity to work in vitro, with primary mammalian cell culture lines and in vivo in zebrafish. The successful candidate will join a newly established enthusiastic team working within a thriving community of cell biology research labs working on various aspects of membrane dynamics and cell signalling.

For more information please email: Dr Bernadette Carroll ([Email Address Removed])

Funding Notes

3-year PhD studentship. The funding covers stipend at UKRI rate and tuition fees at the Home/EU rate for the 3-year duration of studies.

References

• Carroll B, Nelson G, Kucheryavenko, O, Dunhill-Turner NA, Chesterman CC, Zahari Q, Maddocks ODK, Lovat P, von Zglinicki T, Korolchuk VI. Persistent mTORC1 activity supports senescent cell survival. Journal of Cell Biology 2017 3;216(7):1949-1957 (https://rupress.org/jcb/article/216/7/1949/39029/Persistent-mTORC1-signaling-in-cell-senescence)
• Carroll B & Korolchuk, V. Nutrient sensing, growth and senescence. The FEBS Journal 2018 285(11):1948-1958 (https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.14400)
• Carroll, B., Maetzael, D., Maddocks ODK., et al and Korolchuk, VI. Control of TSC2-Rheb signalling axis by arginine regulates mTORC1 activity. eLife 2016 10.7554/eLife.11058 (https://elifesciences.org/articles/11058)
• Correia-Melo et al (2016) Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J 35(7):724-42 (https://www.ncbi.nlm.nih.gov/pubmed/26848154)



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