The Rac1 GTPase plays a pivotal role in the pathogenesis of ischemic and reperfusion injury. Rac1 is activatedduring ischemia/hypoxia and reoxygenation/reperfusion, and by leading to the production of reactive oxygenspecies (ROS) promotes injury and inflammation. However, the molecular mechanisms leading to the activation ofracl during hypoxia/ischemia and reoxgenation/reperfusion are not known.P66shc belongs to the shcA family of adaptor proteins. It is unique among she proteins by virtue of its ability tosense extracellular oxidative stimuli and accordingly govern intracellular levels of reactive oxygen species(ROS).The mechanism by which p66shc regulates intracellular ROS levels is not fully characterized, and the importanceof p66shc in mediating oxidative stress during hypoxia/ischemia and reoxygenation/reperfusion is not known.Based on novel preliminary data, this Project advances the concept that there exists a fundamental relationshipbetween Rac1 and p66shc, and that this relationship is a primary determinant of racl activity and ROS productionduring ischemia/hypoxia and reperfusion/reoxygenation. We hypothesize that ischemia/hypoxia leads to anincrease in expression and activity of p66shc, which, in turn, promotes ROS generation by stimulating the activityof the racl GTPase. Proposed experiments will examine the role of p66shc in ROS production and cardiovascularinjury, the molecular mechanism through which p66shc activates racl, and the molecular regulation of p66shcexpression, during cardiovascular ischemia/hypoxia and reperfusion/hypoxia. These studies will be performed atthe molecular, cellular, and whole animal levels, using gene transfer, and gene knockdown methods, and shouldtherefore provide an in-depth understanding about the importance of p66shc, and its mechanisms, in ischemic andpost-ischemic cardiovascular injury.
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