Endothelial Redox State & Phenotype in Health & Disease

描述（由申请人提供）： 内皮细胞在血管系统中处于拓扑平衡状态，以感知和响应许多环境信号，包括活性氧（ROS）。这些化学活性分子在正常的稳态信号传导中起重要作用;它们的氧化损伤潜力通过精心设计的抗氧化防御系统得到改善。随着ROS通量的增加，内皮细胞通过增强保护机制作出反应，导致代偿性应激状态;当ROS通量进一步增加时，这些保护机制不堪重负，导致非代偿性氧化应激状态。在这个项目申请中，五个项目负责人聚集在一起，研究健康和疾病中内皮细胞氧化信号传导和适应氧化应激的机制。Keaney的项目集中于作为内皮细胞氧化还原信号传导的重要组成部分的foxon; Loscalzo的项目阐述了葡萄糖-6-磷酸脱氢酶及其酶产物NADPH作为内皮细胞中巯基氧化还原状态的关键决定因素的作用;沃尔什的项目研究了Foxo转录因子在促进内皮祖细胞对氧化应激的抵抗中的作用; Cohen的项目考虑了Ras的ROS依赖性氧化修饰对内皮细胞中胰岛素信号传导的影响;项目5测试了线粒体功能障碍和由此产生的氧化应激导致人类动脉粥样硬化中内皮功能障碍的假设。这个概念上有凝聚力的计划汇集了五个建立良好的项目负责人谁拥有生产合作的悠久历史，专注于内皮细胞生物学的一个关键主题。利用当代细胞和分子生物学方法，以及遗传动物模型和人类研究，将在分子和细胞水平上剖析机制，并应用于哺乳动物系统。通过这项提议中提出的工作，我们希望能够确定新的方法来理解氧化剂信号传导的生物分子基础以及氧化应激在内皮（病理）生物学和血管疾病中的适应性和适应不良后果。

DESCRIPTION (provided by applicant): The endothelial cell is topologically poised in the vasculature to sense and respond to a host of environmental signals, including reactive oxygen species (ROS). These chemically active molecules serve important roles in normal, homeostatic signaling; and their potential for oxidative injury is ameliorated by an elaborate system of antioxidant defenses. As the flux of ROS increases, the endothelial cell responds by enhancing protective mechanisms, leading to a state of compensated stress; when the flux of ROS increases further, these protective mechanisms are overwhelmed, leading to a state of uncompensated oxidant stress. In this program project application, five project leaders have come together to investigate mechanisms that underlie oxidant signaling and adaptation to oxidant stress in the endothelial cell in health and disease. Project by Keaney focuses on the mitochondrion as an important component of endothelial redox signaling; Project by Loscalzo addresses the role of glucose-6- phosphate dehydrogenase and its enzymatic product, NADPH, as key determinants of the thiol redox state in the endothelial cell; Project by Walsh examines the role of Foxo transcription factors in promoting resistance to oxidant stress in endothelial progenitor cells; Project by Cohen considers the effect of ROS dependent oxidative modifications of Ras on insulin signaling in the endothelial cell; and Project 5 tests the hypothesis that mitochondrial dysfunction and resulting oxidant stress contribute to endothelial dysfunction in human atherosclerosis. This conceptually cohesive program brings together five well established project leaders who have a long history of productive collaboration to focus on a key theme in endothelial cell biology. Using contemporary methods of cell and molecular biology, as well as genetic animal models and human studies, mechanisms will be dissected at the molecular and cellular levels and applied to mammalian systems. With the work proposed in this proposal, we hope to be able to identify novel approaches to understanding the biomolecular basis of oxidant signaling and the adaptive and maladaptive consequences of oxidant stress in endothelial (patho) biology and vascular disease.