ProtATonce: Signalling and secretome analysis for biomarker discovery and compound evaluation during ageing
i. Objective of research: To use a proprietary multiplexing platform to quantify thousands of proteins in primary human cells entering replicative senescence and mouse progeroid cells that are also exposed to a series of senolytic drugs.
ii. Current state of the art: Senescent cells are known to secrete toxic chemicals that damage adjacent cells. Accumulation of senescent cells, which increases with age, is associated with chronic pathological manifestations, including diabetes, cardiovascular disease, cancer, dementia, arthritis, osteoporosis, and frailty. Recent research strategies aim at using senolytic drugs to target and likely eliminate selectively senescent cells. As senolytic drugs and drug combinations are gradually being discovered, there is immense need to challenge such senolytic regimens for their efficacy in selectively removing senescent cells, for triggering undesirable cytotoxic effects in neighboring cells as well as for rescuing well defined pathological symptoms that gradually manifest with old age.
iii. Research methodology and approach: Our ESR will use a proprietary multiplexing scheme and algorithms to monitor thousands of proteins simultaneously in replicative senescence primary human cells, primary cells derived from NER progeroid mice and their respective culture media. Our ESR will then use a multi-omics network analysis to identify mechanism-based biomarkers. Once a battery of well-defined biomarkers has been established, our ESR will treat cells with a series of carefully selected senolytic drugs and assess to monitor their efficacy. At a subsequent step, our ESR will test the efficacy of senolytic drugs in progeroid mice and asses their impact on age-related metabolic alterations and the premature onset of pathological manifestations, including diabetes, neurodegenerative disorders and lipodystrophy.
iv. Originality and innovative aspects of the ESR project: Rationalized intervention strategies heavily depend on reliable biomarkers to assess their efficacy and toxicity. The proposed research approach offers a robust technological platform to assess the efficacy and drug toxicity of relevant senolytic drugs, nutraceuticals or more specialized regimens that are aimed for future use in clinical trials.
v. Integration of the ESR project to the overall research programme: Our ESR will work with Genevia for the development of new bioinformatics pipelines, with the Garinis group on pro-inflammatory markers and with UNIOVI on senescence-associated biomarkers.