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: 2733163
• 负责人: PAUL G HEYWORTH
• 金额: $ 15.69万
• 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 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2733163
• 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：在对各种刺激的反应中，吞噬细胞