Regulation of endothelial NADPH oxidase by the cytoskeleton

细胞骨架对内皮 NADPH 氧化酶的调节

• 批准号: 7347544
• 负责人: VISWANATHAN NATARAJAN
• 金额: $ 43.83万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7347544
• 关键词: 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; Actins; Acute; Adhesions; Annona muricata coronin; Binding; Blood Vessels; Cells; Chimeric Proteins; Cytoskeleton; DNA Sequence Rearrangement; Development; Endothelial Cells; Functional disorder; Generations; Glutathione S-Transferase; Human; Hyperoxia; Link; MYLK gene; Mediating; Monomeric GTP-Binding Proteins; Myosin Light Chains; NAD(P)H oxidase; NADPH Oxidase; Numbers; Oxidases; Pathway interactions; Peptides; Phagocytosis; Phosphatidic Acid; Phosphatidylinositol 4,5-Diphosphate; Phospholipase D; Phosphorylation; Phosphotransferases; Principal Investigator; Production; Reactive Oxygen Species; Regulation; Respiratory Burst; Rho-associated kinase; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Superoxides; Transfection; cell growth; coronin protein; cytotoxicity; human AKAP13 protein; human EMS1 protein; lung injury; migration; mutant; neutrophil; neutrophil cytosol factor 67K; prevent; programs; pulmonary artery endothelial cell; rho; second messenger

While differences between vascular and phagocytic NADPH oxidase are yet to be identified, reactive oxygen species (ROS) have emerged as important regulatory molecules which function as critical second messengers modulating signal transduction pathways involved in endothelial cell growth, migration, adhesion and barrier function. While actin cytoskeleton has been implicated in phagocytosis and oxidative burst in neutrophils, very little is known regarding the role of actin cytoskeleton in endothelial NAD[P]H oxidase assembly and activation. Our preliminary studies demonstrate that acute hyperoxia-mediated activation of NAD[P]H oxidase and enhanced production of superoxide is regulated by cortical actin cytoskeleton rearrangement, phosphorylated myosin light chain, small G-proteins and phosphatidic acid. We hypothesize that acute hyperoxia-induced endothelial NAD[P]H oxidase activation is mediated by signal transduction pathways regulating cortical actin cytoskeleton remodeling and by facilitating the assembly of the oxidase sub-components. The following specific aims will investigate the relationship between acute hyperoxia, actin cytoskeletal remodeling and NAD[P]H oxidase assembly and activation in human pulmonary artery endothelial cells in the absence of cytotoxicity. SA#1: Will investigate pathways linking actin cytoskeleton remodeling in NAD[P]H oxidase activation; SA#2: Will characterize the role of myosin light-chain phosphorylation in NAD[P]H oxidase activation; SA#3: Will define the role of cortactin and coronin in endothelial NAD[P]H oxidase activation and SA#4: Will characterize the role of phospholipase D / phosphatidic acid signaling in endothelial NAD[P]H oxidase activation. An understanding of the role of actin cytoskeletal remodeling in NAD[P]H oxidase assembly and activation will allow development of targeted therapies to modulate ROS-induced signaling and prevent lung injury and endothelial dysfunction.

尽管尚未确定血管和吞噬NADPH氧化酶之间的差异，但活性氧（ROS）已成为重要的调节分子，这些分子充当关键的第二使者，可调节参与内皮细胞生长，迁移，粘附，粘附和障碍功能的涉及的信号转导途径。虽然肌动蛋白细胞骨架与中性粒细胞中的吞噬作用和氧化爆发有关，但对于肌动蛋白细胞骨架在内皮NAD [P] H氧化酶的组装和激活中的作用而言，知之甚少。我们的初步研究表明，急性高氧介导的NAD [P] H氧化酶的激活和超氧化物的增强受到皮质肌动蛋白肌动蛋白细胞骨架重排调节，磷酸化的肌球蛋白轻链，小的G蛋白和磷脂酸。 我们假设急性高氧诱导的内皮NAD [P] H氧化酶活性是通过调节皮质肌动蛋白细胞骨架重塑的信号转导途径介导的，并通过促进氧化酶亚成分的组装。以下特定目的将研究急性高氧，肌动蛋白细胞骨架重塑和NAD [P] H氧化酶的组装以及在没有细胞毒性的情况下人类肺动脉内皮细胞中的激活。 SA＃1：将研究连接NAD [P] H氧化酶激活中肌动蛋白细胞骨架重塑的途径； SA＃2：将表征肌球蛋白轻链磷酸化在NAD [P] H氧化酶活性中的作用； SA＃3：将定义Cortactin和Coronin在内皮NAD [P] H氧化酶激活和SA＃4中的作用：将表征磷脂酶D /的作用 内皮NAD [P] H氧化酶激活中的磷脂酸信号传导。了解肌动蛋白细胞骨架重塑在NAD [P] H氧化酶组装和激活中的作用将使靶向疗法开发以调节ROS诱导的信号传导并防止肺损伤和内皮功能障碍。