Molecular Regulation of Atherosclerosis

动脉粥样硬化的分子调控

基本信息

批准号：
10331317
负责人：
Hong Chen
金额：
$ 82.27万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10331317
关键词：
Actins Address Anabolism Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Attenuated Autophagocytosis Binding Biological Assay Cell Death Cessation of life Cholesterol Consequentialism Cytoskeleton Development Diet Disease Down-Regulation Eating Endocytosis Endothelial Cells Endothelium Foam Cells Functional disorder Goals Heart Diseases Homing Human Hyperplasia Impairment Inflammation Investigation Knock-out Knockout Mice Knowledge Lesion Lipids Lipoproteins Liquid substance Mass Spectrum Analysis Mediating Medical Mission Modeling Molecular Molecular Target Mus Myelogenous Myocardial Infarction Pathway interactions Peptides Phase Phenotype Play Prevention approach Prevention program Process Property Regulation Research Resolution Risk Factors Role Rupture Signal Pathway Stroke Testing Therapeutic Thrombosis Translating Ubiquitin United States United States National Institutes of Health Work atherogenesis atheroprotective attenuation endothelial dysfunction epsin epsin 1 fight against fighting genetic regulatory protein human disease inhibitor insight lipid mediator macrophage mortality mouse model mutant novel novel strategies novel therapeutic intervention oxidized low density lipoprotein polymerization prevent receptor receptor mediated endocytosis targeted treatment uptake western diet

项目摘要

ABSTRACT Despite effective lipid-lowering therapies and prevention programs, atherosclerosis is still the leading cause of mortality in the United States. Among prominent risk factors, hardening of arteries resulting from endothelial cell activation and neointima hyperplasia plays a causative role in promoting atherogenicity. More importantly, in advanced atheroma, macrophage dysfunction causing excessive cell death is responsible for plaque rupture, consequential thrombosis, and ultimate stroke and myocardial infarction. However, owing to scarcity of proper molecular targets, it is widely recognized that hindering dysfunctional endothelium and macrophages to prevent atherosclerosis remains daunting. Our long-term goal is to uncover molecular mechanisms and identify fresh targets that prevent endothelial and macrophage dysfunction in hopes of offering potential new therapeutic approaches. To this end, our historical efforts have centered on examining the role of endothelial epsins in atherogenesis. In this application, we posit to explore the function of myeloid specific epsins in atherosclerosis owing to the fundamental contribution lesion macrophages make to fuel atherogenicity. The scientific premise for our aforesaid original research is in part established from an intriguing observation that epsins are upregulated in lesion macrophages. Therefore, understanding whether and how macrophage epsins critically contribute to the progression of atherosclerosis is urgently necessitated. We now create novel myeloid-specific epsins deficient mouse models and discover that myeloid-specific deficiency of epsins markedly inhibits western diet induced atherosclerosis in ApoE-/- mice. Further, epsins loss in macrophages dramatically impairs foam cell formation, hinders receptor-mediated oxLDL uptake, and perturbs actin-driven non-receptor mediated endocytosis. In parallel, loss of macrophage epsins results in elevated SR-B1, while diminished SR-B1 abrogates atheroprotective autophagy. Therefore, whether macrophage epsins inhibit autophagy by downregulating SR-B1 is an entirely novel question. To test, we propose to determine molecular mechanisms 1) by which epsins regulate lipid uptake during foam cell formation and 2) underlying epsin- mediated SR-BI degradation and autophagy attenuation in macrophages, and determine macrophage-derived pro-resolving lipid mediator biosynthesis. We anticipate that upon successful completion of the proposed studies, vast knowledge gained will advance the field encompassing how epsins regulate foam cell formation by controlling non-receptor and receptor-mediated lipid uptake, and how SR-B1 and epsins function opposingly to modulate atheroprotective autophagy in macrophages. Moreover, given extremely limited knowledge of the macrophage-derived pro-resolving lipid mediator involved in atherosclerosis, the study proposed herein is poised to provide insights into new means that can be exploited to treat atherosclerosis. If fruitful, our findings will uncover original roles for macrophage epsins in atherosclerosis, offer a new class of therapeutic strategies by targeting epsins, and inaugurate a paradigm shift in research highly relevant to fighting heart disease.

抽象的尽管有效降低脂质疗法和预防计划，但动脉粥样硬化仍然是在美国的死亡率。在突出的危险因素中，内皮产生的动脉硬化细胞激活和新内膜增生在促进动脉粥样硬化性中起致病作用。更重要的是，在晚期动脉粥样硬化中，巨噬细胞功能障碍导致过度细胞死亡导致斑块破裂，结果性血栓形成，最终中风和心肌梗塞。但是，由于稀缺适当的分子靶标，人们广泛认识到，将功能障碍的内皮和巨噬细胞阻碍预防动脉粥样硬化仍然令人生畏。我们的长期目标是发现分子机制并确定预防内皮和巨噬细胞功能障碍的新鲜目标，希望提供潜在的新治疗方法。为此，我们的历史努力集中在检查内皮的作用上动脉粥样硬化中的Epsin。在此应用中，我们假设探索髓样特定Epsin的功能由于病变巨噬细胞对动脉粥样硬化的造成病变的基本贡献，动脉粥样硬化。这我们上述原始研究的科学前提部分是从一个有趣的观察中确定的 EPSIN在病变巨噬细胞中上调。因此，了解巨噬细胞是否以及如何急切需要急需急诊动脉粥样硬化的进展。我们现在创作小说髓样特异性EPSIN缺乏小鼠模型，发现Epsins的髓样特异性缺陷明显抑制西方饮食会诱导APOE - / - 小鼠的动脉粥样硬化。此外，巨噬细胞中的Epsins损失急剧损害泡沫细胞的形成，阻碍受体介导的OXLDL摄取，而perturbs肌动蛋白驱动非受体介导的内吞作用。同时，巨噬细胞Epsins的损失导致SR-B1升高，而 SR-B1减少可消除动脉保护自噬。因此，巨噬细胞Epsin是否抑制通过下调SR-B1的自噬是一个完全新颖的问题。要测试，我们建议确定分子机制1）epsin在泡沫细胞形成过程中调节脂质摄取和2）基础Epsin- 巨噬细胞中介导的SR-BI降解和自噬衰减，并确定巨噬细胞的衍生促分解脂质介质生物合成。我们预计在成功完成拟议的研究，获得的广泛知识将推进遍历epsins如何调节泡沫细胞形成的领域通过控制非受体和受体介导的脂质摄取，以及SR-B1和Epsins的功能如何相反调节巨噬细胞中的动脉保护自噬。而且，鉴于对巨噬细胞衍生的促促脂质脂质介质参与动脉粥样硬化，此处提出的研究是准备提供有关可以利用的新手段来治疗动脉粥样硬化的新手段的见解。如果富有成果，我们的发现将在动脉粥样硬化中发现巨噬细胞Epsin的原始角色，提供新的治疗策略通过瞄准epsin，并启动了与心脏病高度相关的研究范式转变。