The discovery of nitric oxide (NO) in 1987 unraveled the novel concept that an endogenous production of a gaseous substance such as NO can impart diverse and critical functional effects on a wide spectrum of biological and pathological processes. Investigations focused on NO have led to numerous fruitful discoveries, enhancing our understanding of many disease processes including lung disorders. Interestingly though, we have known for a longer period of time that there exists another gaseous molecule, carbon monoxide (CO), which can be generated endogenously; that is, the heme oxygenase (HO) enzyme system generates the majority, if not, all of the endogenous CO. Ironically, CO has been classified as a toxic molecule, lethal to aerobic life and is one of the primary pollutants in industrial society. Against this known paradigm however, interest in CO, akin to the gaseous molecule NO, has recently emerged due to the increasing reports that CO can serve as a signaling molecule in various cellular and biological processes. Our laboratory has reported during the last 5 years that CO serves as a potent cytoprotective molecule with potent anti-inflammatory, anti-apoptotic, and anti-proliferative effects in various models of tissue and cellular injury. The critical challenge facing investigators in this field is to delineate the mechanism by which the gaseous molecule CO mediates its cytoprotective effects. Our recent studies (see Preliminary Studies) highlight the formal possibility that the gaseous molecule CO can provide cytoprotection via its potent anti-apoptotic effect. Hence, we have chosen for this proposal to address the critical question: what is the mechanism by which CO confers potent anti-apoptotic effects in vascular cell and tissue injury? We hypothesize that CO regulates anti-apoptotic effects by activation of the stress response gene HSP70 via the p38 pathway. We further hypothesize that CO-induced HSP70 activation in turn modulate the mitochondrial dependent apoptotic machinery including the Bcl2 family members, apoptosome, and downstream caspases, rather than the death receptor dependent pathway. We will test the hypothesis by addressing the following specific aims:
Specific Aim #1 : To determine the mechanism by which CO activates HSP70 in vitro and in vivo.
Specific Aim #2 : To determine the function of CO-induced HSP70 activation in vitro and in vivo.
Specific Aim #3 : To determine the mechanism by which CO-induced HSP70 activation confers cytoprotection against apoptosis in vitro and in vivo.
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