Role of Drebrin in Atherosclerosis

Drebrin 在动脉粥样硬化中的作用

• 批准号: 8613555
• 负责人: JONATHAN A STIBER
• 金额: $ 27.48万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-14 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8613555
• 关键词: Actin-Binding Protein; Actins; Affect; Agonist; Angiotensin II; Apolipoprotein E; Arterial Fatty Streak; Arterial Injury; Atherosclerosis; Binding; Biological Assay; Blood Vessels; Calcium; Calcium Signaling; Cations; Cell Proliferation; Congestive Heart Failure; Cytoskeleton; Diet; Disease; Exhibits; F-Actin; Family; G Actin; Genes; Homer 1; Hyperplasia; Knowledge; Lead; Link; Measurement; Medical; Microfilaments; Mission; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Neonatal; Pathogenesis; Phenotype; Physiological; Platelet-Derived Growth Factor; Protein Isoforms; Proteins; Public Health; Regulation; Research; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Staining method; Stains; Stroke; Testing; Vascular Smooth Muscle; Vascular remodeling; Wild Type Mouse; burden of illness; cell motility; cell transformation; congenic; disability; drebrins; enhancing factor; feeding; link protein; migration; mortality; mutant; novel therapeutic intervention; public health relevance; receptor; research study; response; scaffold

Integral to the pathogenesis of atherosclerosis is the transformation of vascular smooth muscle cells (SMCs) from a "contractile" to a "proliferative/migratory" phenotype, and growing evidence supports the view that factors enhancing SMC proliferation and migration also enhance atherosclerosis. On a molecular level, this SMC transformation involves cytoskeletal signaling and calcium signaling pathways, which are significantly modulated by calcium influx through transient receptor potential (TRP) channels-a family of nonselective cation channels in SMCs that upregulate when SMCs transition from the contractile to the proliferative/migratory phenotype. Activation of TRP channels is influenced by the underlying cytoskeleton and scaffolding proteins. Unresolved important questions include what proteins link TRP channels to cytoskeletal signaling pathways and how these proteins influence SMC migration. We have previously shown that TRP channels require the scaffolding protein Homer 1 for proper function, and that Homer 1 associates with Drebrin, an actin-binding protein highly expressed in SMCs. In our Preliminary Studies, we found that Drebrin expression is upregulated both during neointimal hyperplasia triggered by arterial injury and in atherosclerotic lesions of Apoe-/- mice, suggesting a role for Drebrin in the regulation of vascular remodeling during atherosclerosis. Compared with wild-type (WT) SMCs, SMCs from Drebrin haploinsufficient (Dbn-/+) mice migrate faster and have increased basal and PDGF-evoked TRP channel activity. Congruently, we found that Dbn-/+ mice developed more neointimal hyperplasia than WT mice in response to carotid endothelial denudation. Gene products that affect neointimal hyperplasia triggered by arterial injury almost invariably affect atherosclerosis in a concordant manner. For this reason we will test the hypothesis that Drebrin activity inhibits atherosclerosis as it inhibits neointimal hyperplasia. Moreover, because of the importance of TRP channels in SMC migration and the importance of Drebrin/Homer scaffolds in regulating TRP channels, we will test the hypothesis that the Drebrin inhibits SMC transformation to the proliferative/migratory phenotype through regulation of TRP channel function. To do so, we will pursue the following Specific Aims: (1) To determine whether Drebrin limits SMC migration/proliferation through regulation of TRP channel activity. We hypothesize that Drebrin reduces SMC migration/proliferation through inhibition of TRP channel activity. (2) To determine whether Drebrin reduces SMC migration through its effects on calcium signaling or through a direct effect on cytoskeletal remodeling. We hypothesize that Drebrin reduces SMC migration through inhibition of calcium signaling. (3) To determine whether Drebrin expression reduces atherosclerosis. We hypothesize that Drebrin reduces atherosclerosis by inhibiting SMC migration/proliferation.

动脉粥样硬化的发病机理不可或缺的是血管平滑肌细胞（SMC）的转化 从“收缩”到“增殖/迁徙”表型，越来越多的证据支持这样的观点 增强SMC增殖和迁移的因素也会增强动脉粥样硬化。在分子水平上， SMC转化涉及细胞骨架信号传导和钙信号通路，这是显着的 通过瞬时受体电势（TRP）通道调节 - 非选择性的家族 SMC中的阳离子通道在SMCS从收缩到收缩过渡到何时上调 增殖/迁移表型。 TRP通道的激活受到潜在的细胞骨架的影响和 脚手架蛋白。未解决的重要问题包括哪些蛋白质链接TRP通道与细胞骨架 信号通路以及这些蛋白质如何影响SMC迁移。我们以前已经证明了TRP 通道需要脚手架蛋白质荷马1才能正确功能，而本垒打1与 Drebrin，一种在SMC中高度表达的肌动蛋白结合蛋白。在我们的初步研究中，我们发现Drebrin 在动脉损伤和动脉粥样硬化触发的新内膜增生期间，表达均上调 apoe - / - 小鼠的病变，暗示了Drebrin在调节血管重塑过程中的作用 动脉粥样硬化。与野生型（WT）SMC相比，来自Drebrin单倍弹性（DBN - /+）小鼠的SMC 迁移更快，增加了基础和PDGF诱发的TRP通道活动。一致，我们发现 DBN-/+小鼠在响应颈动脉内皮方面发展了比WT小鼠更多的新内膜增生 剥夺。影响动脉损伤触发的新内膜增生的基因产物几乎总是总是 以一致的方式影响动脉粥样硬化。因此，我们将测试Drebrin活性的假设 抑制动脉粥样硬化，因为它抑制了新的增生。而且，由于TRP的重要性 SMC迁移中的通道以及Drebrin/Homer脚手架在调节TRP渠道中的重要性，我们将 测试DREBRIN抑制SMC转化为增殖/迁移表型的假设 通过调节TRP通道函数。为此，我们将追求以下具体目标：（1） 确定Drebrin是否通过调节TRP通道活性来限制SMC迁移/增殖。我们 假设Drebrin通过抑制TRP通道活性来降低SMC迁移/增殖。 （2）至 确定Drebrin是通过对钙信号的影响还是通过直接来减少SMC的迁移 对细胞骨架重塑的影响。我们假设Drebrin通过抑制来降低SMC的迁移 钙信号传导。 （3）确定Drebrin表达是否减少了动脉粥样硬化。我们假设这一点 Drebrin通过抑制SMC迁移/增殖来减少动脉粥样硬化。