Vascular Signaling by Free Radicals

最近，许多报道在许多不同的水平上定义了活性氧（ROS）或血管生物学的作用。许多报告提供证据表明ROS介导血管壁的多种信号事件，包括；内皮和血管肌细胞中的离子通道活性，细胞内第二信使的激活/抑制，蛋白质磷酸化，粘附分子的激活，有丝分裂途径的激活/抑制。拟议的计划项目拨款（PPG）将从遗传；细胞、分子、离子和全动物水平上ROS介导/修改血管信号事件调节血管功能、血管生成和细胞凋亡的机制。项目1由David Harder博士指导，将测试ROS启动和/或修改调节脑血流（CBF）的信号事件的假设。他的实验室将研究ROS通过离子通道活性和小动脉肌2信使的激活对脑血管信号的作用，确定自由基在小动脉肌2信使的自调节中的作用，确定自由基在CBF的自调节中的作用，以及对神经活动的反应中的功能性充血。最后，项目1将确定ROS在大脑星形胶质细胞介导的毛细血管生成中的作用。项目II由David Gutterman博士指导，将确定ROS在介导血流（剪切）诱导的人类冠状动脉扩张中的作用。Gutterman博士已经证明，在人类冠状动脉中，EDHF在剪切诱导的扩张中起着重要作用，并提供了令人信服的数据表明ROS参与了这一反应。由William Chilian博士领导的项目III将确定ROS对内皮离子通道的作用，这些通道负责设置和维持膜电位。Chilian博士及其同事将探索一种新的假设，即o2通过内皮ci通道移动，这可能在抗氧化防御机制中发挥作用。彼得·纽曼博士将指导第四项目并检验PECAM-1是自由基的目标这一假设。Newman的研究小组已经证明H2O2诱导酪氨酸残基的磷酸化和oono硝化作用可以激活和抑制PECAM-1。PECAM-1是一种具有抑制剂受体特性的粘附分子，自由基调节PECAM-1活性是影响细胞-细胞相互作用和多种细胞信号通路的重要过程。项目V由Balaraman Kalyanaraman博士领导，将探索ROS在内皮和血管有丝分裂活动中起关键作用的假设。本课题将研究NO和ROS对氧化LDL诱导的细胞凋亡的作用。Kalyanaraman博士及其同事将定义Ros的矛盾效应，即Ros在血管壁中启动和抑制细胞增殖。这些项目将依靠自由基和分析化学核心来测量和操纵自由基，并测量细胞信号分子。这个程序汇集了一个关键的测量细胞信号分子。该计划汇集了大量公认的研究人员和最先进的技术，以确定活性氧和氮物种在血管生物学中的生物学作用。

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.