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

项目摘要/摘要 动脉粥样硬化是包括心肌梗塞在内的大多数心血管疾病的根本原因。 脑梗塞、中风和心力衰竭在世界范围内导致巨大的发病率和死亡率。风险因素 减肥、降低高脂血症和高血压等调整措施是唯一的预防措施 对这种令人烦恼的疾病有可用的策略。因此，有一个积极的努力，以确定罪魁祸首的细胞过程 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 动脉粥样硬化中的自噬-溶酶体系统。各种不同的证据表明， 斑块巨噬细胞自噬-溶酶体系统功能障碍提示 重新编程巨噬细胞的降解能力可能是一个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 它在巨噬细胞中的作用导致动脉粥样硬化的减少。TFEB的一个关键目标是自噬 伴侣p62/SQSTM1，介导细胞毒性蛋白聚集体的去除。我们的工作表明 清除巨噬细胞中富含p62的货物是一种新的治疗策略。在具体目标1中，我们 将决定巨噬细胞中主要依赖p62的自噬过程，这些过程是TFEB- 介导的动脉粥样硬化保护作用。在特定的目标2中，我们探索了hsp104，a，a的潜在的动脉粥样硬化保护作用。 新的解聚酶系统主要研究在简单的生物体中。这种方法将是对 自噬研究，因为它是一种完全不依赖于自噬的清除巨噬细胞蛋白的机制 集合体。总体而言，这项提议将检验利用巨噬细胞降解剂的假设 对透明蛋白聚集体的反应可能是治疗动脉粥样硬化的一种新方法。

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.