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Senescence and the SASP: implications in cancer and ageing

  • Full or part time
  • Application Deadline
    Sunday, December 01, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Senescence is a cellular response to stresses such as oncogenic signalling, DNA damage and telomere loss, characterized by a stable growth arrest. The importance of senescence as a safeguard against malignant transformation has been broadly studied for over 10 years. More recently, senescence has also been implicated in numerous other biological processes, wherein senescence may be beneficial, such as for maintenance of tissue homeostasis or detrimental such as in organismal ageing and, paradoxically, cancer progression. These detrimental effects have been linked to the secretion by senescent cells of a collection of factors that include cytokines and chemokines with pro-inflammatory properties, as well as various growth factors and proteases. Collectively, this is known as the senescence-associated secretory phenotype (SASP). Given the relevance of senescence itself and the SASP in influencing aging, cancer and other diseases, to understand how they are regulated is the first step to target them therapeutically. In this regard, SASP modulation or the selective killing of senescent cells (senolytic approraches) have been proposed as effective approaches.

One of our interests is the identification of genes and compounds influencing senescence and the SASP. A general approach that we take is to perform genetic and drug screens. We intend to identify novel genes that regulate different aspects of senescence. Initially, we aim to define the molecular mechanisms underlying the action of these genes and how they relate to core tumour suppressor networks such as the p16/Rb, p53 pathway and the inflammatory SASP. Eventually, we want to interrogate which role do these genes have in cancer and aging and whether they are therapeutic targets (as senolytics or SASP inhibitors) relevant for cancer and ageing. To this end we combine cell culture experiments, animal models and the analysis of their expression in human samples.

To Apply: Please visit our website (https://lms.mrc.ac.uk/study-here/phd-studentships/lms-3-5yr-studentships/) to download an application form.

Funding Notes

This project is one of multiple available projects potentially funded by the MRC. If successful the studentship would cover all tuition fee payments and includes a tax-free stipend amounting to £21,000pa (paid in monthly installments directly to the student) for 3.5 years.

Whilst this funding is available to students worldwide, due to the higher tuition fee rate of overseas students competition is higher and so only exceptional OS applicants will be considered.

References

• Guerrero et al. 2019. Cardiac glycosides are broad-spectrum senolytics. Nature Metabolism, in press

• Georgilis et al. 2018. PTBP1-mediated splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells. Cancer Cell, 34, 85-102.

• Gil and Withers. 2016. Ageing: Out with the old, Nature 530, 164-165.

• Herranz et al. 2015. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nature Cell Biology 17, 1205-1217.

• Acosta et al. 2013. A complex secretory response orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biology, 15, 978-990.
• O’Loghlen et al. 2012. The miR-125 and miR-181 microRNA families regulate ES cell differentiation by targeting the Polycomb protein Cbx7. Cell Stem Cell, 10, 33-46
• Kang et al. 2011. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551.
• Acosta et al. 2008. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018.

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