Phospholipase D2 regulation of vascular smooth muscle cell migration

磷脂酶 D2 对血管平滑肌细胞迁移的调节

基本信息

批准号：
8696936
负责人：
GUANGWEI DU
金额：
$ 38万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696936
关键词：
Address Affect Angioplasty Angiotensin II Animal Model Atherosclerosis Binding Proteins Biology Blood Vessels Cardiovascular Diseases Cell Polarity Cell physiology Cells Cellular biology Chronic Disease Cytoskeletal Modeling Data Development Enzymes Event Family Figs - dietary Functional disorder Genetic Hydrolysis Immigration In Vitro Injury Knockout Mice Lead Lecithin Lipids Liposomes Mass Spectrum Analysis Membrane Membrane Microdomains Membrane Protein Traffic Methods Microfilaments Microtubules Molecular Molecular Biology Morbidity - disease rate Motor Mus Patients Phosphatidic Acid Phospholipase D Phospholipids Platelet-Derived Growth Factor Play Positioning Attribute Process Proteins Reagent Recruitment Activity Regulation Research Role Signal Pathway Signal Transduction Signaling Molecule Site Smooth Muscle Myocytes Stents Testing Tunica Adventitia Vascular Diseases Vascular remodeling Vesicle Work base cell motility cell type experience in vivo inhibitor/antagonist insight interdisciplinary approach member migration mortality mouse model novel novel therapeutics phospholipase D2 prevent public health relevance response response to injury restenosis vascular smooth muscle cell migration

项目摘要

DESCRIPTION (provided by applicant): The migration of vascular smooth muscle cells (VSMCs) is an essential event during atherosclerosis and restenosis after angioplasty. Cellular migration is achieved through coordinated regulation of membrane trafficking and cytoskeletal reorganization. While many studies have focused on the regulation of cytoskeletal reorganization in VSMCs, little is known about the involvement of membrane trafficking and the coordinated regulation of cytoskeletal reorganization and membrane trafficking in the migration of these cells. Our preliminary data have suggested that Phospholipase D2 (PLD2), a member of the phospholipase D family that generates the signaling lipid phosphatidic acid (PA), plays important roles in the migration, cytoskeletal reorganization, and membrane trafficking in VSMCs. Using a combination of liposome pull-down and mass spectrometry, we also identified some new PA-binding proteins, which have revealed the novel mechanistic insights into the cellular functions of PA. Based on our findings, we propose that PLD2-generated PA coordinately regulate cytoskeletal reorganization and membrane trafficking during VSMC migration. By using some newly available reagents and a unique interdisciplinary approach including molecular and cell biology, lipid biology, and animal models, we will investigate the mechanisms by which PLD2 regulates VSMC migration in vitro, and then examine how PLD2-regulated cell migration contributes to injury-induced vascular remodeling using mouse models. Three aims are proposed. In Aim 1, we will examine the roles of PLD2 in the polarization and migration of VSMCs. In Aim 2, we will elucidate the mechanisms by which PLD2-controlled membrane trafficking regulates VSMC migration. In Aim 3, we will investigate if PLD2 regulates vascular remodeling in vivo.

描述（由申请人提供）：血管平滑肌细胞（VSMC）的迁移是动脉粥样硬化和血管成形术后再狭窄期间的重要事件。细胞迁移是通过膜运输和细胞骨架重组的协调调节来实现的。虽然许多研究都集中在 VSMC 中细胞骨架重组的调节上，但人们对膜运输的参与以及细胞骨架重组和膜运输在这些细胞迁移中的协调调节知之甚少。我们的初步数据表明，磷脂酶 D2 (PLD2) 是磷脂酶 D 家族的成员，可产生信号脂质磷脂酸 (PA)，在 VSMC 的迁移、细胞骨架重组和膜运输中发挥重要作用。通过结合脂质体下拉和质谱分析，我们还鉴定了一些新的 PA 结合蛋白，这些蛋白揭示了 PA 细胞功能的新机制。根据我们的研究结果，我们提出 PLD2 产生的 PA 协调调节 VSMC 迁移过程中的细胞骨架重组和膜运输。通过使用一些新的试剂和独特的跨学科方法，包括分子和细胞生物学、脂质生物学和动物模型，我们将在体外研究PLD2调节VSMC迁移的机制，然后研究PLD2调节的细胞迁移如何导致损伤-使用小鼠模型诱导血管重塑。提出了三个目标。在目标 1 中，我们将研究 PLD2 在 VSMC 极化和迁移中的作用。在目标 2 中，我们将阐明 PLD2 控制的膜运输调节 VSMC 迁移的机制。在目标 3 中，我们将研究 PLD2 是否调节体内血管重塑。