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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：
10521273
负责人：
Hong Chen
金额：
$ 78.59万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10521273
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Adaptor Signaling Protein Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Binding Binding Proteins Blood Cardiovascular Diseases Cause of Death Cell Adhesion Molecules Cessation of life Cholesterol Chronic Complement Coronary heart disease Deposition Development Diet Disease Down-Regulation Dyslipidemias Encapsulated Endothelial Cells Endothelium Event FOXO1A gene Foam Cells Functional disorder Generations Genetic Transcription Goals Growth Hepatocyte Human Hyperlipidemia Incidence Inflammation Ischemic Stroke Knowledge LDL Cholesterol Lipoproteins Lesion Life Life Style Lipids Liver Low Density Lipoprotein Receptor Macrophage Mass Spectrum Analysis Mediating Medicine Mission Modeling Modernization Molecular Mus Mutant Strains Mice Myelogenous Myocardial Infarction Nuclear Import Oxidoreductase Patients Peripheral arterial disease Persons Predisposition Prevention program Production Reagent Regulatory Element Research Resolution Risk Factors Role Rupture Signal Pathway Signal Transduction Site Small Interfering RNA Sterols Stroke Subendothelial Layer Testing Therapeutic Triglycerides Ubiquitination United States United States National Institutes of Health Work atherogenesis attenuation blood lipid cell injury design effective therapy epsin epsin 1 field study fighting fortification in vitro Model inhibitor innovation monocyte mouse model nanoparticle new therapeutic target next generation novel novel strategies novel therapeutic intervention oxidized lipid oxidized low density lipoprotein prevent protective effect protein activation protein expression recruit targeted treatment therapeutic evaluation therapeutic target transcription factor transcriptome sequencing translational potential ubiquitin ligase vascular inflammation western diet

项目摘要

PROJECT SUMMARY/ABSTRACT Atherosclerosis is the leading cause of life-threatening coronary heart disease, ischemic stroke, and peripheral arterial disease in the United States. Notably, dyslipidemia remains a major risk factor despite effective lipid- lowering therapies and prevention programs. This is, in part, due to overwhelming arterial inflammation that drives the transition from a stable to vulnerable and rupture-prone atheroma. The lack of effective therapies to lower circulating cholesterol while forcefully curbing arterial inflammation during atheroma progression presents an opportunity to develop innovative, new medicines for this devastating disease. Understanding the causative molecular mechanisms responsible for dyslipidemia and arterial inflammation should provide for the rapid development of more potent therapeutic approaches. Our long-term goal is to uncover molecular mechanisms underlying the pathophysiology and unearth fresh potential therapeutic targets. Much of our earlier research has centered on examining the role of epsin endocytic adaptor proteins in endothelial cells and macrophages to regulate progression of atherogenesis. We have demonstrated that epsins 1 and 2 are upregulated in atherosclerotic plaques in mouse models of atherosclerosis and human atherosclerotic lesions. Consequently, deletion of epsins in the endothelium and macrophages resulted in marked attenuation of atherogenesis. Mechanistically, we showed that epsins escalate arterial inflammation by expressing adhesion molecules, enhancing monocyte recruitment, and hindering efferocytosis. More recently, we created a liver- specific deficiency of epsins in an atherosclerotic mouse model and found that atherogenesis was greatly inhibited and accompanied with diminished blood cholesterol levels and triglyceride levels. Therefore, targeting epsins, their binding partners, and downstream targets represents an attractive therapeutic approach to resolve both chronic vascular inflammation and dyslipidemia associated with atheroma development. In this new application, our proposal builds on compelling evidence that epsins contribute to hyperlipidemia by enhancing sterol regulatory element binding protein (SREBP) transcriptional activity to promote cholesterol synthesis as well as increasing low density lipoprotein receptor (LDLR) degradation to perturb oxidized lipid clearance in the liver. By targeting liver epsins using nanoparticle-encapsulated siRNAs, we hope to design a novel therapeutic strategy to impede dyslipidemia in atherosclerosis. We will investigate the following Specific Aims using unique mutant mice, in vitro models, and novel reagents: 1) to determine the molecular mechanisms by which liver epsins regulate SREBPs in atherosclerosis, 2) to determine the molecular mechanisms of liver epsin-mediated downregulation of LDLR in atherosclerosis, and 3) to determine the therapeutic potential of targeting liver epsins for atheroma resolution. If fruitful, our findings will uncover original roles for liver epsins in fueling hyperlipidemia in atherosclerosis, offer a new class of therapeutic strategies for treating this disease, and inaugurate a paradigm shift in research relevant to fighting cardiovascular disease.

项目总结/摘要动脉粥样硬化是危及生命的冠心病、缺血性中风和外周血管疾病的主要原因。动脉疾病在美国。值得注意的是，血脂异常仍然是一个主要的危险因素，尽管有效的血脂- 降低治疗和预防计划。这部分是由于压倒性的动脉炎症，促使动脉粥样硬化从稳定状态转变为脆弱和易破裂的状态。缺乏有效的治疗方法，降低循环胆固醇，同时有力地抑制动脉粥样硬化进展期间的动脉炎症这是一个为这种毁灭性疾病开发创新新药的机会。了解引起血脂异常和动脉炎症的分子机制应该提供快速发展更有效的治疗方法。我们的长期目标是揭示病理生理学的潜在机制，并发掘新的潜在治疗靶点。我们的大部分早期的研究集中在检测内皮细胞中epsin内吞衔接蛋白的作用，巨噬细胞调节动脉粥样硬化的进展。我们已经证明，epsins 1和2是在动脉粥样硬化小鼠模型和人动脉粥样硬化病变中的动脉粥样硬化斑块中上调。因此，内皮细胞和巨噬细胞中epsin的缺失导致内皮细胞和巨噬细胞中epsin的显著减弱。动脉粥样硬化从机制上讲，我们发现，胰蛋白酶通过表达粘附，分子，增强单核细胞募集和阻碍单核细胞增多。最近，我们制造了一个肝脏- 在动脉粥样硬化小鼠模型中特异性缺乏胰蛋白酶，并发现动脉粥样硬化形成大大抑制并伴有血液胆固醇水平和甘油三酯水平降低。因此，针对 epsins、它们的结合伴侣和下游靶点代表了一种有吸引力的治疗方法，解决与动脉粥样硬化发展相关的慢性血管炎症和血脂异常。在这新的应用，我们的建议建立在令人信服的证据，epsins有助于高脂血症，增强固醇调节元件结合蛋白（SREBP）转录活性以促进胆固醇合成以及增加低密度脂蛋白受体（LDLR）降解以扰乱氧化脂质肝脏清除率。通过使用纳米颗粒包裹的siRNA靶向肝epsin，我们希望设计一种阻止动脉粥样硬化中血脂异常的新治疗策略。我们将调查以下具体情况目的：使用独特的突变小鼠、体外模型和新型试剂：1）确定肝胰蛋白酶调节动脉粥样硬化中SREBP的机制，2）确定分子水平，动脉粥样硬化中肝epsin介导的LDLR下调的机制，以及3）确定靶向肝epsin用于动脉粥样硬化消退的治疗潜力。如果富有成果，我们的发现将揭示原创性肝胰蛋白酶在动脉粥样硬化高脂血症中的作用，提供了一类新的治疗策略，治疗这种疾病，并开创了与心血管疾病斗争相关的研究范式转变。