HOW DOES RAC CONTROL HUMAN PHAGOCYTE NADPH OXIDASE?

RAC 如何控制人类吞噬细胞 NADPH 氧化酶？

• 批准号: 2895357
• 负责人: PAUL G HEYWORTH
• 金额: $ 16.32万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2001-01-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895357
• 关键词: NAD(P)H dehydrogenase; actins; animal tissue; biological signal transduction; cell free system; cell membrane; chronic granulomatous disease; electron transport; enzyme activity; enzyme complex; enzyme inhibitors; enzyme structure; guanine nucleotide binding protein; guanosinetriphosphatase activating protein; guanosinetriphosphatases; human tissue; immunoprecipitation; intermolecular interaction; leukocyte oxidative burst; molecular site; myeloid stem cell; neutrophil; phosphorylation; protein purification; protein structure function; superoxides

DESCRIPTION: In response to a variety of stimuli, phagocytic cells undergo a respiratory burst, catalyzed by an NADPH oxidase complex that reduces oxygen to (superoxide is O2-). Superoxide and its metabolites are essential for killing bacteria, fungi and parasites. The importance of NADPH oxidase is made very apparent by the inherited syndrome chronic granulomatous disease (CGD), in which oxidase activity is absent and affected individuals are susceptible to life-threatening infections. In contrast to this beneficial role, O2- and its derivatives can cause severe tissue damage, contributing to inflammatory diseases such as ischemia-reperfusion injury and adult respiratory distress syndrome. The prolonged generation of oxygen radicals by phagocytes, in situations of chronic inflammation, can also lead to dysplasia and malignant transformation. The long term objectives of the proposed research are therefore 1) to understand fully the mechanisms that regulate NADPH oxidase assembly and activity, and 2) to identify steps that can be pharmacologically manipulated, either to enhance oxidase activity during severe infections or to inhibit its activity and minimize tissue damage. The specific aims of the proposed research are: 1) To identify the functional target(s) of Rac in NADPH oxidase regulation; 2) To determine the role of Rac in regulating the assembly and activation of NADPH oxidase; 3) To identify the site(s) of phosphorylation of Rac2 and define the functional relationship between its phosphorylation and NADPH oxidase activation; 4) To identify and purify GTPase activating protein(s) for Rac and to study their involvement in the control of Rac and NADPH oxidase activity. These studies may reveal possible targets for therapeutic intervention in a mechanism central to the control fo phagocyte NADPH oxidase, as well as contributing to general models for the role of GTP-binding proteins in regulating metabolic systems.

描述：对各种刺激的反应，吞噬细胞 经历呼吸爆发，由NADPH氧化酶络合物催化 将氧气还原为(超氧化物为O2-)。超氧化物及其代谢物 杀灭细菌、真菌和寄生虫所必需的。它的重要性 遗传综合征使NADPH氧化酶的表达变得非常明显 慢性肉芽肿性疾病(CGD)，其中氧化酶活性 缺席和受影响的人容易受到生命危险的影响 感染。与这种有益的作用相反，O2-及其衍生物 会导致严重的组织损伤，导致炎症 缺血再灌注损伤和成人呼吸道等疾病 窘迫综合症。氧自由基长时间的产生 吞噬细胞，在慢性炎症的情况下，也可以导致 不典型增生和恶变。长期目标 因此，拟议研究的主要目的是：1)充分了解 调节NADPH氧化酶组装和活性的机制，以及2) 为了确定可以在药物上操纵的步骤， 在严重感染期间增强氧化酶活性或抑制其 并最大限度地减少对组织的损害。《公约》的具体目标 拟开展的研究有：1)确定Rac的功能靶点(S)。 NADPH氧化酶的调节；2)确定Rac在调节中的作用 NADPH氧化酶的组装和激活；3)定位(S) 并确定了其功能关系。 它的磷酸化和NADPH氧化酶活性之间的关系；4) RAC和TO GTP酶激活蛋白(S)的鉴定和纯化 它们参与调控RAC和NADPH氧化酶的研究 活动。这些研究可能揭示出可能的目标 控制口蹄疫的核心机制中的治疗性干预 吞噬细胞NADPH氧化酶，以及对 GTP结合蛋白在调节代谢系统中的作用。