DESCRIPTION (provided by applicant): Proliferative senescence of cultured cells is a useful model system to study aging in vitro. In vivo, senescent cells accumulate in aging tissues and at sites of age-related pathologies such as atherosclerotic lesions and preneoplastic lesions, raising the possibility that senescent cells may promote the aging phenotype or age-related pathologies. Indeed, senescent cells were shown to secrete proteins that can alter the function and architecture of the surrounding tissues. In addition to normal cells, tumor cells also undergo proliferative senescence upon treatment with chemotherapeutic drugs. Importantly, many genes that are induced in senescent tumor cells encode secreted proteins with both tumor-promoting and tumor-suppressing activities, which can affect the prognosis of tumor patients. Therefore, the emerging hypothesis is that protein secretion from senescent cells mediates the in vivo aging process and age-related pathologies, as well as the tumor response to therapy. In this context, it is important to note that only a small number of studies have been carried out on proteins secreted from senescent cells and that we still lack comprehensive knowledge of the secretory patterns of normal as well as tumor cells undergoing senescence. Employing a novel quantitative proteomics technology, ICAT (isotope-coded affinity tag), we have developed a method to systematically identify and quantify proteins secreted in culture supernatant, and using this method, we analyzed the secretory pattern of human fibroblasts undergoing replicative senescence. We propose to extend this analysis by 1) comparing the secretory patterns of senescent fibroblasts induced to senesce by different mechanisms, by 2) comparing the secretory patterns of senescent fibroblasts and senescent endothelial cells, and by 3) analyzing the secretory patterns of tumor cells induced to senesce by chemotherapeutic drug treatment. The secretory patterns of senescent cells identified through this exploratory project will provide a basis for future investigations on the fundamental principles governing aging processes as well as more effective treatment and prevention of age-related diseases and cancer.
|Effective start/end date||2/15/07 → 1/31/10|
- National Institutes of Health: $146,657.00
- National Institutes of Health: $149,650.00