Vascular Signaling by Free Radicals

最近，许多报告已经定义了活性氧（ROS）或血管生物学的作用，在许多不同的水平。这些报告中的许多提供了ROS介导血管壁中的多种信号传导事件的证据，包括：离子通道活性、细胞内第二信使的激活/抑制、蛋白磷酸化、粘附分子的激活、内皮细胞和血管肌肉细胞中促有丝分裂途径的激活/抑制。拟议的计划项目资助（PPG）将开始在遗传;细胞，分子，离子和整个动物水平的机制，通过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。项目1由大卫哈德博士指导，并将测试ROS启动和/或修改调节脑血流（CBF）的信号事件的假设。他的实验室将通过离子通道活性和小动脉肌肉中第二信使的激活来研究ROS对脑血管信号传导的作用，定义自由基在小动脉肌肉中第二信使的自动调节中的作用，定义自由基在CBF自动调节中的作用，以及响应神经活动的功能性充血。最后，项目I将确定活性氧在修饰星形胶质细胞介导的脑毛细血管生成中的作用。 由大卫Gutterman博士指导的项目II将定义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参与了这种反应。由William Chilian博士领导的项目III将定义ROS对负责设置和维持膜电位的内皮离子通道的作用。Chilian博士及其同事将探索新的假设，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。Peter New man博士将指导项目IV，并将测试PECAM-1是自由基目标的假设。纽曼的小组已经表明，过氧化氢诱导磷酸化和酪氨酸残基的OONO-硝化，激活和抑制PECAM-1。PECAM-1是一种具有抑制剂受体性质的粘附分子，自由基对PECAM-1活性的调节是影响细胞间相互作用和多种细胞信号传导途径的重要过程。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。本课题旨在研究NO和ROS在氧化LDL诱导的细胞凋亡中的作用。Kalyanaraman博士及其同事将定义ROS的Ros效应的矛盾效应，以启动和抑制血管壁中的细胞增殖。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。该计划汇集了细胞信号分子的关键措施。该计划汇集了大量公认的研究人员和最先进的技术，以确定活性氧和氮在血管生物学中的生物作用。

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.