ENDOTHELIUM AND VASCULAR FUNCTION

描述（由申请人提供）： 该计划项目资助申请描述了我们计划作为我们以前的心血管功能调节项目的延续进行的研究，主要是通过内皮源性介质，一氧化氮和活性氧。本申请建立在我们以前的 获得的数据，以进一步确定这些药物在控制血管和心脏功能中的作用。我们的总体假设是，我们的目标是测试的氧自由基物种，通过激活血管壁中的氮氧化物氧化酶，通过引起一氧化氮生物利用度的降低，加速血管功能障碍的发展，导致疾病。在第一个项目中，Wolin博士将描述Nox相关的信号传导 机制影响血管功能，以及这些机制在病理生理条件下如何改变。 在第二个项目中，Hintze博士将在小鼠，大鼠和狗中研究NADPH氧化酶在继发于钠限制的氧化剂产生增加中的作用，这是一种与血管紧张素产生增加相关的状态。他还将在狗心脏中确定钠限制对冠状循环的NO依赖性调节的影响以及底物的命运和代谢酶表达的改变。在第三个项目中，Kaley博士计划研究衰老对2型糖尿病患者血管功能的影响。 糖尿病（db/db）和eNOS-KO小鼠，两种不同的代谢综合征模型，每种模型的特征在于氧化应激增加和一氧化氮生物利用度降低。这些项目将得到三个核心的支持;一个由Edwards博士领导，提供小鼠的基因分型和生理测量，一个由Ungvari博士领导，他将提供血管和组织中ROS成像的专业知识。 一个是由Ojaimi博士领导的，他将解释通过基因阵列技术获得的数据。我们相信，我们的研究将提供概念上的进步，可能会导致更好地了解疾病状态下血管功能障碍的发展以及新的治疗选择。

DESCRIPTION (provided by applicant): This Program Project Grant application describes studies we plan to perform as a continuation of our previous projects concerned with the regulation of cardiovascular function, primarily by endothelium-derived mediators, nitric oxide and reactive oxygen species. The present application builds on our previously obtained data to further establish the role of these agents in the control of vascular and cardiac function. Our overall hypothesis that we aim to test is that oxygen radical species, derived through activation of Nox oxidases in the vessel wall, by causing a reduction in nitric oxide bioavailability, hasten the development of vascular dysfunction leading to disease. In the first Project, Dr. Wolin will characterize how Nox-linked signaling mechanisms affect vascular function and how these mechanisms are altered in pathophysiologic conditions. In the second Project, Dr. Hintze will examine in mice, rats and dogs the role of NADPH oxidase in the increased oxidant production secondary to sodium restriction, a state associated with increased angiotensin production. He will also determine in the dog heart the effects of sodium restriction on NO dependent regulation of the coronary circulation as well as the fate of substrates and the alteration in the expression of metabolic enzymes. In the third Project, Dr. Kaley plans to study the effects of aging on vascular function in type 2 diabetic (db/db) and eNOS-KO mice, two different models of metabolic syndrome, each of which is characterized by increased oxidant stress and a reduction in nitric oxide bioavailability. The projects will be supported by three cores; one led by Dr. Edwards, providing genotyping of and physiologic measurements in mice, one led by Dr. Ungvari who will provide expertise in imaging ROS in vessels and tissues by state of the art methods and one led by Dr. Ojaimi, who will interpret data obtained by gene array techniques. We believe that our research will provide conceptual advances that will likely lead to a better understanding of the development of vascular dysfunction in disease states as well as to novel therapeutic options.