Cigarette smoking is a major cause of chronic obstructive pulmonary diseases (COPD) and accelerates the aging process with premature death due to atherosclerotic diseases and malignancy. Werner's syndrome, a genetic disorder caused by loss-of-function mutations in the Wrn gene encoding a member of RecQ helicase family (WRN protein) also accelerates aging. The aging process is associated with cellular senescence that is a state in which cells are metabolically active, but permanently unable to divide. Both cigarette smoke and WRN protein defects induce cellular senescence. I recently demonstrated that cigarette smoke induces cellular senescence via WRN protein downregulation in cultured human lung fibroblasts. I also showed that N-acetyl cysteine, a thiol antioxidant attenuates cigarette smoke-induced WRN protein downregulation and growth inhibition. These data suggest a potential role of redox regulation in cigarette smoke-induced cellular senescence. My preliminary data showed that aldehyde dehydrogenase (ALDH), a NAD(P)+-dependent enzyme which catalyzes aldehyde oxidation, blocks cigarette smoke-induced DNA damage response and growth inhibition in cultured lung fibroblasts. My proposed research will further investigate mechanisms of cigarette smoke-induced cellular senescence. My central hypothesis is that cigarette smoke induces cellular senescence via reactive aldehyde-mediated WRN protein downregulation. In Aim1, I will first determine if acrolein induces cellular senescence in cultured human lung fibroblasts and airway epithelial cells. I will then determine if acrolein-induced cellular senescence requires WRN protein downregulation. In Aim2, I will determine if total ALDH activity and the individual expression of isozymes including ALDH1A1, ALDH2 and ALDH3A1 are altered in the lung tissue among nonsmokers and smokers with COPD or without COPD. I will also determine if exposure to cigarette smoke extract alters total ALDH activity and the individual isozyme expression in cultured lung fibroblasts and epithelial cells. I will further investigate a potential role of the ALDH isozymes in cigarette smoke-induced WRN protein downregulation and cellular senescence by using an in vitro model. This proposal will help to deepen further understanding of the mechanisms of cigarette smoke-induced cellular senescence and may contribute to novel therapeutic strategies directed at modulating WRN protein expression for smoking-related lung diseases, such as COPD.
|Effective start/end date||07/01/2010 → 06/30/2012|