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Clearance of macrophage p62-enriched protein aggregates as a therapy for Atherosclerosis

清除富含 p62 的巨噬细胞蛋白聚集体作为动脉粥样硬化的治疗方法

基本信息

批准号：
10214664
负责人：
Babak Razani
金额：
$ 39.38万
依托单位：
WASHINGTON UNIVERSITY
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：
2014-11-04 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10214664
关键词：
Apoptotic Area Arterial Fatty Streak Atherosclerosis Autophagocytosis Biogenesis Body Weight decreased Cardiovascular Diseases Cause of Death Cell Death Cell physiology Cells Clinical Complex Coronary Arteriosclerosis Cytoplasm Data Deposition Disease Evaluation Event Excision Fibroblasts Foam Cells Functional disorder Future Genes Goals Heart failure Hydrolysis Hyperactivity Hyperlipidemia Hypertension In Vitro Inclusion Bodies Infiltration Inflammasome Inflammatory Investigation Lipids Lipoproteins Lysosomal Storage Diseases Lysosomes Mediating Membrane Methods Mitochondria Modification Molecular Chaperones Morbidity - disease rate Mus Myocardial Infarction Neurodegenerative Disorders Organelles Organism Pathogenicity Pathway interactions Phagocytosis Phenotype Prevention strategy Process Proteins Proteomics Risk Factors Role Series Signal Transduction Stimulus Stroke System Testing Therapeutic Transgenic Mice Tropism United States Variant Work atherogenesis atheroprotective base cytotoxic cytotoxicity experience in vivo insight interest lipid metabolism macrophage mortality mouse model mutant novel novel strategies novel therapeutic intervention overexpression oxidized low density lipoprotein protein aggregation response transcription factor uptake

项目摘要

Project Summary / Abstract Atherosclerosis is the underlying cause of the majority of cardiovascular diseases including myocardial infarction, strokes, and heart failure leading to tremendous morbidity and mortality worldwide. Risk factor modification such as weight loss, reductions in hyperlipidemia and hypertension constitute the only preventive strategy available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that provide mechanistic insight. Recent work by us and others has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Various lines of evidence demonstrate a progressive dysfunction in the autophagy-lysosome system of plaque macrophages suggesting that attempts at reprogramming the degradative capacity of macrophages might be a fruitful therapeutic area. Our work with TFEB, the predominant transcription factor regulating autophagy-lysosomal biogenesis, shows that enhancing its function in macrophages leads to reductions in atherosclerosis. A critical TFEB target is the autophagy chaperone p62/SQSTM1 which mediates the removal of cytotoxic protein aggregates. Our work has shown that clearance of the p62-enriched cargo in macrophages is a novel therapeutic strategy. In specific aim 1, we will determine the predominant p62-dependent autophagic processes in macrophages that underlie TFEB- mediated atheroprotection. In specific aim 2, we explore the potential atheroprotective benefits of HSP104, a novel disaggregase system mostly studied in simple organisms. This approach will be complementary to the autophagy studies since it is a completely autophagy-independent mechanism of clearing macrophage protein aggregates. Overall, this proposal will test the hypothesis that harnessing the macrophage degradative response to clear protein aggregates can be a novel approach to treat atherosclerosis.

项目总结/摘要动脉粥样硬化是大多数心血管疾病的根本原因，包括心肌梗死。梗塞、中风和心力衰竭导致全球发病率和死亡率极高。危险因素改变，如减肥，减少高脂血症和高血压构成了唯一的预防对付这种令人烦恼的疾病的有效策略。因此，有一个积极的努力，以确定罪魁祸首细胞过程提供机械的洞察力。我们和其他人最近的工作重新引起了人们对自噬-溶酶体系统在动脉粥样硬化中的作用各种证据表明，噬斑巨噬细胞自噬-溶酶体系统功能障碍提示，重编程巨噬细胞的降解能力可能是富有成效的治疗领域。我们的工作与 TFEB，调节自噬-溶酶体生物发生的主要转录因子，表明增强其在巨噬细胞中的功能导致动脉粥样硬化的减少。一个关键的TFEB目标是自噬伴侣蛋白p62/SQSTM 1介导细胞毒性蛋白聚集体的去除。我们的工作表明巨噬细胞中富含p62的货物的清除是一种新的治疗策略。在具体目标1中，我们将决定在TFEB的基础巨噬细胞中主要的p62依赖性自噬过程，介导的动脉粥样硬化保护作用。在具体目标2中，我们探索了HSP 104的潜在动脉粥样硬化保护作用，主要在简单生物体中研究的新型解聚酶系统。这一做法将补充自噬研究，因为它是一个完全自噬独立的机制，清除巨噬细胞蛋白集料.总的来说，这项提案将测试的假设，利用巨噬细胞降解对透明蛋白聚集体的反应可能是治疗动脉粥样硬化的新方法。