Molecular Mechanisms Regulating Epsin-Dependent LRP-1 Internalization and Degradation in Atherosclerosis

调节动脉粥样硬化中 Epsin 依赖性 LRP-1 内化和降解的分子机制

• 批准号: 9196252
• 负责人: Megan Brophy
• 金额: $ 1.8万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196252
• 关键词: Molecular; Mechanisms; Regulating; Epsin; Dependent

 DESCRIPTION (provided by applicant): Atherosclerosis, the process of vascular wall thickening and hardening, is a significant contributing factor in the development of cardiovascular disease (the leading cause of morbidity and mortality in the U.S.). Therefore, understanding the molecular mechanisms involved in atherosclerotic lesion (atheroma) progression has significant relevance in human disease and therapeutic development. We recently identified a novel role for the endocytic adaptor protein, epsin, as a pro-atherogenic and pro-inflammatory regulator in the endothelium. Specifically, we observed that epsins 1 and 2 are upregulated in the aortic atheroma of western diet fed ApoE-/- mice. Furthermore, we found that epsin-depletion in macrophages protects against atherosclerosis in part by impairing lipoprotein accumulation and foam cell development. This phenotype is in direct contrast to that of LRP-1-deficient mice suggesting a link between epsin function and LRP-1 regulation, which has never before been investigated. Therefore, in this proposal we describe a research strategy to test the central hypothesis that epsins interact with and facilitate the internalization of LRP-1, thus impairing efferocytosis and contributing to foam cell maturation and atheroma development. In support, we report that epsin deficiency is associated with increased total and cell surface LRP-1 expression in macrophages in vitro. Furthermore, we have preliminary data suggesting that epsin 1 and LRP-1 interact in vitro. Therefore, we propose a research strategy to characterize the molecular mechanisms by which epsins interact with LRP-1 in macrophages and to determine if this interaction results in the downregulation of LRP-1 resulting in impaired efferocytosis and atheroma development. In summary, the information gained from this proposal will provide a novel regulator, and potential new therapeutic target, for the development and progression of atherosclerosis.

 描述（由申请人提供）：动脉粥样硬化是血管壁增厚和硬化的过程，是心血管疾病（美国发病率和死亡率的主要原因）发展的重要促进因素。因此，了解动脉粥样硬化病变（动脉粥样硬化）进展的分子机制在人类疾病和治疗发展具有重要意义。我们最近发现了一个新的作用，内吞衔接蛋白，epsin，作为一个促动脉粥样硬化， 内皮中的促炎调节剂。具体地，我们观察到，epsin 1和2在西方饮食喂养的ApoE-/-小鼠的主动脉粥样硬化中上调。此外，我们发现，在巨噬细胞中的胰蛋白酶耗竭部分通过损害脂蛋白积累和泡沫细胞发育来保护免受动脉粥样硬化。这种表型与LRP-1缺陷小鼠的表型形成直接对比，表明epsin功能和LRP-1调节之间存在联系，这在以前从未被研究过。因此，在这个建议中，我们描述了一个研究策略，以测试的核心假设，即epsin相互作用，促进LRP-1的内化，从而损害红细胞，并有助于泡沫细胞成熟和动脉粥样硬化的发展。在支持，我们报告，胰蛋白酶缺乏症与增加总的和细胞表面LRP-1在体外巨噬细胞的表达。此外，我们有初步的数据表明，epsin 1和LRP-1在体外相互作用。因此，我们提出了一个研究策略，以表征的分子机制，通过这种相互作用与LRP-1在巨噬细胞中的相互作用，并确定这种相互作用是否会导致LRP-1的下调，从而导致受损的红细胞增多症和动脉粥样硬化的发展。综上所述，本研究为动脉粥样硬化的发生和发展提供了一种新的调节剂和潜在的新的治疗靶点。