The Study of the Effect of Redox Status on Cellular Stress Responses and Growth Regulation

Cellular stress could lead to redox status imbalance. Redox status regulation plays a critical role in cell growth, senescence, aging and pathogenesis of degenerative diseases. If the redox balance is tilted towards production of reactive oxygen species, these highly reactive species alter signal transduction and inflict macromolecular damages, which accumulate throughout the cellular and organismal lifespan. Our previous studies have shown that the G6PD-deficient cells have an increased propensity for replicative senescence and stress-induced senescence. It is associated with increased oxidant production and accumulation of oxidative DNA damage. The interplay between different oxidative damage markers and antioxidant or related metabolites has not been extensively studied. This is one of our interests to elucidate the correlations between different oxidative damage markers and antioxidants and related metabolites in cellular senescence. We plan to carry an in-depth study of cell cycle regulators and growth-related signaling and metabolic pathways. Our preliminary microarray study has revealed transcriptomic changes during cellular senescence of normal and G6PD-deficient cells. Additionally, our metabolomic study also revealed significant changes in metabolites, such as antioxidant-related metabolites, in cells under oxidative stress. However, its relationship between changes in metabolism and cellular senescence remains elusive. To discover any novel regulators of replicative and stress-induced senescence, we plan to continue the microarray analysis, and introduce the proteomic, metabolomic as well as miRNA transcriptomic analyses. Any putative regulators will be cloned, and functionally analyzed using over-expression and knockdown approaches. The implication of ROS in senescence raises the possibility that antioxidants might delay cellular senescence. We aim to examine the long-term effect of antioxidants on cell growth. Additionally, we plan to generate cell lines and transgenic mice expressing shRNA against antioxidant-related genes, and study their phenotypic changes and the underlying mechanisms. Through the present study, we will gain a better understanding of interactions between intracellular redox milieu, signaling, growth and senescence. In addition, any molecules differentially expressed and/or modified during cellular senescence might find their application as markers of aging and degenerative diseases.

Project ID:PC10101-1246
External Project ID:NSC99-2320-B182-021-MY3