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）：血管性平滑肌细胞（VSMC）的迁移是血管成形术后动脉粥样硬化和再狭窄期间的重要事件。通过协调的膜运输和细胞骨架重组来实现细胞迁移。尽管许多研究集中在VSMC中细胞骨架重组的调节，但对膜运输的参与以及对这些细胞迁移的细胞骨架重组和膜运输的协调调节知之甚少。我们的初步数据表明，磷脂酶D2（PLD2）是产生信号脂质脂质磷脂酸（PA）的磷脂酶D家族的成员，在迁移，细胞骨架重组中起着重要作用，在vSMC中发挥了细胞骨架重组和膜运输。我们还结合了脂质体下拉和质谱法，我们还确定了一些新的PA结合蛋白，这些蛋白揭示了对PA细胞功能的新机械见解。根据我们的发现，我们建议PLD2生成的PA协同调节VSMC迁移期间的细胞骨架重组和膜运输。通过使用一些新可用的试剂以及一种独特的跨学科方法，包括分子和细胞生物学，脂质生物学和动物模型，我们将研究PLD2在体外调节VSMC迁移的机制，然后研究PLD2调节的细胞迁移如何有助于使用小鼠模型造成损伤诱导的血管重塑。提出了三个目标。在AIM 1中，我们将研究PLD2在VSMC的极化和迁移中的作用。在AIM 2中，我们将阐明PLD2控制的膜运输调节VSMC迁移的机制。在AIM 3中，我们将研究PLD2是否在体内调节血管重塑。