ENDOTHELIUM AND VASCULAR FUNCTION

描述（由申请人提供）： 本计划项目资助申请描述了我们计划作为我们的继续进行的研究。 以前的项目涉及心血管功能的调节，主要是通过内皮衍生的 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 我们旨在测试的总体假设是，通过活化NOx而衍生的氧自由基物质 血管壁中的氧化酶通过引起一氧化氮生物利用度的降低，加速了 导致疾病的血管功能障碍。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氧化酶在增加的 继发于钠限制的氧化剂产生，一种与血管紧张素增加相关的状态 生产他还将在狗的心脏中确定钠限制对NO依赖性的影响。 调节冠状动脉循环以及底物的命运和表达的改变， 代谢酶在第三个项目中，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，每种模型都是 其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 由三个核心支持;一个由Edwards博士领导，提供基因分型和生理测量， 小鼠，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 我相信，我们的研究将提供概念上的进步，这可能会导致更好地理解 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.