NADPH OXIDASE- REGULATION OF ENDOTHELIAL CELL CYCLE PROGRESSION

内皮细胞的生长、死亡和功能是糖尿病、动脉粥样硬化、心力衰竭甚至衰老等多种疾病的重要决定因素。最近发现，内皮细胞的功能和细胞命运与细胞的氧化还原状态密切相关。受控的内源性活性氧(ROS)的产生对于正常的内皮细胞增殖、血管生成和重塑(细胞周期控制)是绝对必要的。然而，过量的ROS产生会导致内皮功能障碍甚至死亡。内皮细胞结构性地表达一种多组分的NADPH氧化酶，它是产生超氧化物的主要来源。NADPH氧化酶的催化亚基有5种亚型，命名为Nox1-5，其中至少有3种亚基(Nox1、2和4)存在于内皮细胞中。我们的假设是，不同的NADPH氧化酶的NOx亚型可能不同地控制该酶的活性，从而调控内皮细胞的氧化还原状态和命运。该项目的总体目标是研究NADPH氧化酶对内皮细胞周期进程的调控机制。特别是，我们希望研究NOX2和NOX4(NADPH氧化酶的两种主要的NOX亚型)在控制内皮细胞中ROS产生的水平和位置方面的作用的差异，这可能参与细胞增殖、生长停滞甚至死亡的决策过程。该项目将为我们提供关于内皮细胞周期进程的氧化还原调节的基本信息，以及NADPH氧化酶在内皮细胞功能和血管生物学中的作用。

Endothelial cell growth, death and function are important determinant related to many diseases including diabetes, atherosclerosis, heart failure and even aging. Very recently it was discovered that endothelial cell function and cell fate are tightly coupled to the cellular redox state. Controlled endogenous reactive oxygen species (ROS) generation is absolutely necessary for normal endothelial cell proliferation, angiogenesis and remodeling (cell cycle control). However, excessive ROS production causes endothelial dysfunction and even death. Endothelial cells express constitutively a multicomponent NADPH oxidase, which is a major source of superoxide generation. The catalytic subunit of NADPH oxidase has 5 isoforms named Nox1-5, and at least 3 of them (Nox1, 2 and 4) are found in endothelial cells. Our hypothesis is that different Nox isoforms of NADPH oxidase may control differently the activity of this enzyme, and then regulate the redox state and the fate of endothelial cells. The overall aim of the project is to investigate the mechanisms of NADPH oxidase regulation of endothelial cell cycle progression. In particular, we wish to examine the differences in the roles of Nox2 and Nox4 (2 major Nox isoforms of NADPH oxidase) in control the levels and the location of ROS production in endothelial cells, which may be involved in the decision making process of cell proliferation, growth arrest or even death. This project will provide us with the fundamental information on redox-regulation of endothelial cell cycle progression, and the role of NADPH oxidase in endothelial cell function and vascular biology.