Role of Drebrin in Atherosclerosis

Drebrin 在动脉粥样硬化中的作用

• 批准号: 9233179
• 负责人: JONATHAN A STIBER
• 金额: $ 27.83万
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233179
• 关键词: Actin-Binding Protein; Actins; Affect; Agonist; Alpha Cell; Angiotensin II; Apolipoprotein E; Arterial Fatty Streak; Arterial Injury; Atherosclerosis; Binding; Biological Assay; Calcium; Calcium Signaling; Cations; Cell Proliferation; Congestive Heart Failure; Cytoskeleton; 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; United States National Institutes of Health; Vascular Smooth Muscle; Vascular remodeling; Wild Type Mouse; burden of illness; calmodulin-dependent protein kinase II; cell motility; cell transformation; congenic; disability; drebrins; enhancing factor; experimental study; gene product; knock-down; link protein; mortality; mutant; novel therapeutic intervention; public health relevance; receptor; response; scaffold; western diet

DESCRIPTION (provided by applicant): 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 th 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.

描述（由申请人提供）：动脉粥样硬化发病机制的一个组成部分是血管平滑肌细胞（SMC）从“收缩”表型向“增殖/迁移”表型的转变，并且越来越多的证据支持以下观点：促进 SMC 增殖和迁移的因素迁移还会加剧动脉粥样硬化。在分子水平上，这种 SMC 转化涉及细胞骨架信号传导和钙信号传导途径，这些途径受到通过瞬时受体电位 (TRP) 通道的钙流入的显着调节。TRP 通道是 SMC 中的非选择性阳离子通道家族，当 SMC 从收缩型转变为收缩型时，这些通道上调。增殖/迁移表型。 TRP 通道的激活受到底层细胞骨架和支架蛋白的影响。尚未解决的重要问题包括哪些蛋白质将 TRP 通道与细胞骨架信号传导途径连接起来，以及这些蛋白质如何影响 SMC 迁移。我们之前已经证明，TRP 通道需要支架蛋白 Homer 1 才能发挥正常功能，并且 Homer 1 与 Drebrin（一种在 SMC 中高度表达的肌动蛋白结合蛋白）相关。在我们的初步研究中，我们发现Drebrin表达在动脉损伤引发的新内膜增生期间和Apoe-/-小鼠的动脉粥样硬化病变中均上调，表明Drebrin在动脉粥样硬化期间血管重塑的调节中发挥作用。与野生型 (WT) SMC 相比，Drebrin 单倍剂量不足 (Dbn-/+) 小鼠的 SMC 迁移速度更快，并且基础和 PDGF 诱发的 TRP 通道活性增加。一致地，我们发现 Dbn-/+ 小鼠响应颈动脉内皮剥脱比 WT 小鼠出现更多的新内膜增生。影响动脉损伤引发的内膜增生的基因产物几乎总是以一致的方式影响动脉粥样硬化。因此，我们将检验 Drebrin 活性抑制动脉粥样硬化的假设，因为它抑制新内膜增生。此外，由于TRP通道在SMC迁移中的重要性以及Drebrin/Homer支架在调节TRP通道中的重要性，我们将检验Drebrin通过调节TRP通道功能抑制SMC向增殖/迁移表型转化的假设。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 通道活性来减少 SMC 迁移/增殖。 (2) 确定 Drebrin 是否通过其对钙信号传导的影响或通过对细胞骨架重塑的直接影响来减少 SMC 迁移。我们假设 Drebrin 通过抑制钙信号传导来减少 SMC 迁移。 (3)确定Drebrin表达是否减少动脉粥样硬化。我们假设 Drebrin 通过抑制 SMC 迁移/增殖来减少动脉粥样硬化。

项目成果

USP20 (Ubiquitin-Specific Protease 20) Inhibits TNF (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates Atherosclerosis.

• DOI: 10.1161/atvbaha.118.311071
• 发表时间: 2018-10
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Jean-Charles PY;Wu JH;Zhang L;Kaur S;Nepliouev I;Stiber JA;Brian L;Qi R;Wertman V;Shenoy SK;Freedman NJ
• 通讯作者: Freedman NJ