Recently, numerous reports have defined actions of reactive oxygen species (ROS) or vascular biology, at many different levels. Many of these reports provide evidence that ROS mediate a variety of signaling events in the vascular wall including; ion channel activity, activation/inhibition of intracellular 2nd messengers, protein phosphorylation, activation of adhesion molecules, activation/inhibition of mitogenic pathways in endothelial and vascular muscle cells. The proposed Program Project Grant (PPG) will begin at the genetic; cellular, molecular, ionic, and whole animal level the mechanisms through which ROS mediate/modify vascular signaling events regulating vascular function, angiogenesis and apoptosis. Project 1 is directed by Dr. David Harder and will test the hypothesis that ROS act to initiate and/or modify signaling events regulating cerebral blood flow (CBF). His laboratory will study the action of ROS on cerebral vascular signaling through ion channel activity and activation of 2nd messengers in arteriolar muscle, define the role of radicals in autoregulation of 2nd messengers in arteriolar muscle, define the role of radicals in autoregulation of CBF, and functional hyperemia in response to neural activity. Finally, Project I will determine the action of ROS in modifying astrocyte mediated capillary angiogenesis in the brain. Project II directed by Dr. David Gutterman, will define the role of ROS in mediating flow (shear) induced dilation of human coronary arteries. Dr. Gutterman has demonstrated that in human coronary arterioles EDHF plays an important role in shear-induced dilation, and presents convincing data that ROS participate in this response. Project III, lead by Dr. William Chilian will define the action of ROS on endothelial ion channels responsible for setting and maintaining membrane potential. Dr. Chilian and colleagues will explore the novel hypothesis that O2-moves through endothelial CI-channels which may play a role in anti-oxidant defense mechanisms. Dr. Peter New man will direct Project IV and will test the hypothesis that PECAM-1 is a target for free radicals. Newman's group has shown that H2O2 induces phosphorylation, and OONO-nitration of tyrosine residues that activates and inhibits PECAM-1. PECAM-1 is an adhesion molecule with properties of an inhibitor receptor-regulation of PECAM-1 activity by free radicals is an important process that can effect cell-cell interaction and a variety of cellular signaling pathways. Project V is lead by Dr. Balaraman Kalyanaraman and will explore that hypothesis that ROS plays a pivotal role in endothelial and vascular mitotic activity. This project will study the actions of NO and ROS on apoptosis induced by oxidized LDL. Dr. Kalyanaraman and colleagues will define the paradoxical effect of Ros effect of ROS to both initiate and inhibit cellular proliferation in the vascular wall. These Projects will rely on a Free Radical and an Analytical Chemistry Core to measure and manipulate free radicals and to measure cellular signaling molecules. This Program brings together a critical measure cellular signaling molecules. This Program brings together a critical mass of recognized investigators and state-of-art techniques to define the biologic role of reactive oxygen and nitrogen species in vascular biology.
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