Nox1 and Nox4 Containing Oxidases are Required for PDGF-induced Migration of

PDGF 诱导的迁移需要含有 Nox1 和 Nox4 的氧化酶

基本信息

批准号：
7546827
负责人：
Holly Colette Williams
金额：
$ 2.82万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7546827
关键词：
Actins Affect Angioplasty Area Atherosclerosis Blood Platelets Blood Vessels Cardiovascular Diseases Caveolins Cell Nucleus Cell membrane Cell physiology Cells Cytoskeletal Proteins Cytoskeleton Data Disease Progression Drug Delivery Systems Enzymes Family Family member Filopodia Focal Adhesions GTPase-Activating Proteins Gene Expression Growth Factor Guanine Nucleotide Exchange Factors Hormones Hypertension Immigration Inflammatory Injury Lead Localized Mediating Modeling Monomeric GTP-Binding Proteins Mus NADPH Oxidase Oxidases Oxidation-Reduction Pathology Pathway interactions Platelet-Derived Growth Factor Play Process Production Protein Overexpression Proteins Reactive Oxygen Species Receptor Signaling Role Signal Pathway Signal Transduction Signaling Molecule Smooth Muscle Myocytes Source Stress Fibers Testing Therapeutic Vinculin caveolin 1 cell type concept in vivo migration neointima formation novel therapeutics polymerization response restenosis rho rho GTP-Binding Proteins vascular smooth muscle cell migration

项目摘要

DESCRIPTION (provided by applicant): Migration of vascular smooth muscle cells (VSMCs) plays an important role in cardiovascular disease progression. The migration of VSMCs is associated with atherosclerosis and restenosis after angioplasty due to increased neointima formation. Recent studies demonstrate that platelet derived growth factor (PDGF) stimulation promotes ROS formation and migration of VSMCs. ROS act as signaling molecules in cellular pathways that modulate migration, but the source of these ROS, the mechanisms regulating their production, and their downstream targets remain unclear. Here I propose a mechanism by which both Nox1 and Nox4 NADPH oxidases are required for VSMC migration. I hypothesize that PDGF-induced migration in VSMCs requires basal Nox4 activity and Rac-mediated stimulation of Nox1 to modulate focal adhesion dynamics and the actin cytoskeleton. In this proposal, I will evaluate this hypothesis via three aims. In the first aim, I will determine the mechanism by which PDGF activates Rac to stimulate Nox1 and modulate redox sensitive signaling pathways that alter actin polymerization. In aim 2, I will evaluate the role of Nox4 expression and activity on Rho expression and Rho-mediated focal adhesion turnover in VSMCs. The third and final aim will test some of these concepts in vivo by examining the role of Nox4 in neoinitmal formation. Understanding the mechanism by which PDGF induces VSMC migration is very important to developing therapeutic strategies to combat cardiovascular disease.

描述（由申请人提供）：血管平滑肌细胞（VSMC）的迁移在心血管疾病进展中起重要作用。 VSMC的迁移与动脉粥样硬化和血管成形术后的动脉粥样硬化有关，这是由于新内膜形成增加而导致的。最近的研究表明，血小板得出的生长因子（PDGF）刺激促进了VSMC的ROS形成和迁移。 ROS在调节迁移的细胞途径中充当信号分子，但是这些ROS的来源，调节其产生的机制以及其下游靶标仍然不清楚。在这里，我提出了一种机制，VSMC迁移需要NOX1和NOX4 NADPH氧化酶。我假设PDGF诱导的VSMC迁移需要基础NOX4活性和RAC介导的NOX1刺激以调节局灶性粘附动力学和肌动蛋白细胞骨架。在此提案中，我将通过三个目标评估这一假设。在第一个目标中，我将确定PDGF激活RAC刺激NOX1并调节改变肌动蛋白聚合的氧化还原敏感信号通路的机制。在AIM 2中，我将评估Nox4表达和活性对VSMC中RHO表达和RHO介导的局灶性粘附的作用。第三个也是最后一个目标将通过研究NOX4在NeoInitmal形成中的作用来测试其中一些概念。了解PDGF诱导VSMC迁移的机制对于制定治疗策略来打击心血管疾病非常重要。