"The Role of Signaling Adaptor Protein Epsin in Atherosclerosis"

“信号转接蛋白 Epsin 在动脉粥样硬化中的作用”

基本信息

批准号：
9198034
负责人：
Hong Chen
金额：
$ 44.13万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2014-01-20 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198034
关键词：
Ablation Acute Adaptor Signaling Protein Address Affect Alleles Animal Model Apolipoprotein E Arterial Fatty Streak Atherosclerosis Binding Binding Proteins Biological Models Cardiovascular Diseases Carotid Arteries Cause of Death Cell Adhesion Molecules Cells Clathrin Clathrin Adaptors Clathrin-Coated Vesicles Complex Dangerousness Development Disease Down-Regulation Due Process Employee Strikes Endocytosis Endothelial Cells Family Flow Cytometry Genes Genetic Growth Human Immune Immunofluorescence Immunologic Immunohistochemistry In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Ischemia Lead Lesion Leukocyte Trafficking Light Link Low Density Lipoprotein oxidation Mediating Medicine Membrane Proteins Modeling Molecular Mus Mutant Strains Mice Myocardial Infarction NF-kappa B P-Selectin Pathogenesis Pathway interactions Peptides Peripheral Pharmacology Play Process Production Proteins Reagent Receptor Signaling Recruitment Activity Role Rupture Signal Transduction Small Interfering RNA Stroke TNF gene TRADD gene TRAF2 gene Testing Therapeutic Intervention Thrombosis Tissues Translating Tumor Necrosis Factor Receptor Ubiquitin United States Vascular Cell Adhesion Molecule-1 atherogenesis attenuation base chemokine cytokine epsin epsin 1 hypercholesterolemia in vivo in vivo Model inhibitor/antagonist knock-down novel promoter public health relevance targeted treatment therapeutic evaluation western diet

项目摘要

DESCRIPTION (provided by applicant): The arterial inflammatory responses initiated by the oxidation of LDL trapped in the subendothelium are a key process that drives the initiation, progression, and even rupture of atherosclerotic plaques. However, there have been no effective medicines or therapies available to disrupt the inflammatory process due to lack of appropriate targets. Epsins are a group of proteins that bind clathrin and are involved in the endocytosis of clathrin-coated vesicles. Our studies have shown that epsins expressed in endothelial cells play a major role in the pathogenesis of atherosclerosis. Deletion of the epsin 1 (Epn1) and epsin 2 (Epn2) genes in endothelial cells results in a dramatic reduction in atherosclerotic lesion sizes in apolipoprotein E-deficient (ApoE-/-) mice without affecting systemic hypercholesterolemia. We have also observed that knockdown of both Epn1 and Epn2 with siRNAs affects NF-kB signaling transduction and suppresses both baseline and TNFa-induced VCAM-1 and P-selectin expression in endothelial cells. Therefore, we hypothesize that epsins critically regulate arterial inflammatory responses and consequently potentiate atherosclerotic plaque formation by enhancing TNF-induced NF-kB activation. The role of epsins 1 and 2 in atherosclerosis and molecular mechanisms underlying the arterial inflammatory processes will be characterized using both in vitro and in vivo model systems. In Aim 1, we will investigate molecular mechanisms by which epsins enhance TNF-induced NF-kB signaling in endothelial cells. In Aim 2, we will utilize multifactorial approaches employing both flow cytometry and immunohistochemistry and immunofluorescence to investigate how epsins promote atherogenesis by potentiating endothelial cell activation. These studies will provide mechanistic links between epsins and plaque formation. In Aim 3, we will determine whether targeting epsins in plaques impedes atheroma progression in ApoE-/- mice. These studies will shed light on new pathways that control atherosclerosis and may lead to new treatment of atherosclerosis.

描述（申请人提供）：由内皮下层中的 LDL 氧化引发的动脉炎症反应是驱动动脉粥样硬化斑块发生、进展甚至破裂的关键过程。然而，由于缺乏适当的靶点，目前还没有有效的药物或疗法可以破坏炎症过程。 epsins 是一组结合网格蛋白并参与网格蛋白包被囊泡的内吞作用的蛋白质。我们的研究表明，内皮细胞表达的epsins在动脉粥样硬化的发病机制中发挥着重要作用。删除epsin 1 内皮细胞中的 Epsin 2 (Epn1) 和 Epsin 2 (Epn2) 基因可显着减少载脂蛋白 E 缺陷 (ApoE-/-) 小鼠的动脉粥样硬化病变大小，而不影响全身性高胆固醇血症。我们还观察到，用 siRNA 敲低 Epn1 和 Epn2 会影响 NF-kB 信号转导，并抑制内皮细胞中基线和 TNFa 诱导的 VCAM-1 和 P-选择素表达。因此，我们假设 Epsins 关键性地调节动脉炎症反应，从而通过增强 TNF 诱导的 NF-kB 激活来增强动脉粥样硬化斑块的形成。 epsins 1 和 2 在动脉粥样硬化中的作用以及动脉炎症过程的分子机制将使用体外和体内模型系统进行表征。在目标 1 中，我们将研究 epsins 增强内皮细胞中 TNF 诱导的 NF-kB 信号传导的分子机制。在目标 2 中，我们将利用流式细胞术、免疫组织化学和免疫荧光等多因素方法来研究 epsins 如何通过增强内皮细胞活化来促进动脉粥样硬化形成。这些研究将提供epsins和斑块形成之间的机制联系。在目标 3 中，我们将确定针对斑块中的 Epsins 是否会阻碍 ApoE-/- 小鼠的动脉粥样硬化进展。这些研究将揭示控制动脉粥样硬化的新途径，并可能带来动脉粥样硬化的新治疗方法。