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Hypoxic regulation of senescent cells secretome in lung cancer and Alzheimer's disease

Objective

Research over the last decade has convincingly evidenced that cellular senescence and low oxygen (O2) availability (hypoxia) are distinctive features involved in the physiopathology of age-related disorders including lung cancer and Alzheimer’s disease (AD). Cellular senescence is characterised by a permanent and irreversible cell cycle arrest and the acquisition of an intense senescence associated secretory phenotype (SASP). Mounting evidence has shown that the SASP accounts for most of the detrimental effects of senescent cells accumulated in aged tissues. Therefore, understanding the mechanisms that modulate the composition and intensity of the SASP is a fundamental biological question with significant translational implications in age-related disorders.
Senescent cells accumulate in tissues where O2 is very limited. To live under these conditions, senescent cells must adapt to hypoxia via the stabilisation of hypoxia inducible transcription factor (HIF). I hypothesise that local hypoxia determines the composition and intensity of the SASP in age-related disorders, a concept that I will name hSASP. Given the intrinsic heterogeneity of the SASP across tissues, I will test this hypothesis in lung cancer and AD models where there is a concomitant accumulation of senescent cells in hypoxic areas. I will use a variety of genotoxic agents to induce cellular senescence in lung cancer and stromal cells as well as in murine primary astrocytes exposed to a decreasing range of O2 tensions. I will elucidate the role of hypoxia in regulating the composition and intensity of the hSASP and its paracrine effects on nearby cells. Finally, I will identify relevant hSASP factors and define their functional effects on lung cancer and microglial cells.
Targeting specific hSASP factors may offer new therapeutic opportunities to attenuate the adverse effects of senescent cells accumulated in age-related disorders such as lung cancer or AD.

Call for proposal

H2020-MSCA-IF-2020
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Coordinator

FUNDACION PUBLICA ANDALUZA PARA LAGESTION DE LA INVESTIGACION EN SALUD DE SEVILLA
Address
Avenida Manuel Siurot Hospitales Universitarios Virgen Del Rocio
41013 Sevilla
Spain
Activity type
Research Organisations
EU contribution
€ 172 932,48