Mechanisms of Abeta-Stimulated ROS in Microglia

小胶质细胞中 Abeta 刺激 ROS 的机制

• 批准号: 6885427
• 负责人: BRANDY L WILKINSON
• 金额: $ 4.73万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-11-01 至 2007-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885427
• 关键词: NAD(P)H dehydrogenase; amyloid proteins; biological signal transduction; cell surface receptors; enzyme activity; enzyme mechanism; free radical oxygen; laboratory mouse; microglia; nerve injury; oxidative stress; postdoctoral investigator; protein transport; protein tyrosine kinase; receptor expression

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate mechanisms mediating the microglia pro-inflammatory response to fibrillar beta amyloid (fAa). The interaction of microglia with Abeta plaques leads to the induction of proinflammatory signaling cascades and the release of neurotoxic secretory products. Previous studies have shown fAbeta-stimulated ROS production from the activation of microglial NADPH oxidase. The NADPH oxidase consists of the membrane associated flavoprotein cytochrome b558 and the cytosolic, p47phox, p67phox, p40phox, and Rac1. Rac must be GTP-bound to function as part of the oxidase. The cytosolic components, p47phox and p67phox, under go phosphorylation and translocation to the membrane to initiate ROS generation. Little is known about the Abeta-stimulated intracellular signaling pathways responsible for this activation. We hypothesize that fAbeta engagement of a newly discovered multireceptor cell surface complex on microglia leads to the production of ROS and subsequent neuronal damage. This proposal seeks to identify tyrosine kinase-based signaling cascades that activate intracellular signaling elements that function to stimulate assembly and activation of the NADPH oxidase following exposure to fAbeta.

描述（由申请人提供）： 该提案的目的是阐明介导对纤维β淀粉样蛋白（FAA）的小胶质细胞促炎反应的机制。小胶质细胞与Abeta斑块的相互作用导致促炎信号级联反应和神经毒性分泌产物的释放。先前的研究表明，小胶质细胞NADPH氧化酶激活Fabeta刺激了ROS的产生。 NADPH氧化酶由膜相关的黄蛋白细胞色素B558和胞质，p47phox，p67phox，p40phox和rac1组成。 RAC必须与GTP结合才能作为氧化酶的一部分发挥作用。在GO磷酸化和易位向膜的胞质成分，P47Phox和P67Phox下启动ROS的产生。关于负责这种激活的ABETA刺激的细胞内信号通路知之甚少。我们假设在小胶质细胞上新发现的多受体细胞表面复合物的Fabeta参与会导致ROS的产生和随后的神经元损伤。该建议旨在鉴定基于酪氨酸激酶的信号传导级联反应，该级联激活细胞内信号传导元件，这些元素在暴露于Fabeta后功能刺激组装和激活NADPH氧化酶的激活。