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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：
10318660
负责人：
Hong Chen
金额：
$ 78.57万
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/10318660
关键词：
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 Hydroxymethylglutaryl-CoA reductase Hyperlipidemia Incidence Inflammation Ischemic Stroke Knowledge LDL Cholesterol Lipoproteins Lesion Life Life Style Lipids Liver Low Density Lipoprotein Receptor Mass Spectrum Analysis Mediating Medicine Mission Modeling Modernization Molecular Mus Mutant Strains Mice Myelogenous Myocardial Infarction Nuclear Import Patients Peripheral arterial disease Persons 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 in vitro Model inhibitor innovation macrophage 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/文摘