Harnessing the Autophagy-Lysosomal Biogenesis Response in Macrophages to Treat Atherosclerosis

项目摘要和摘要 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 诸如降低高脂血症和高血压等改进措施是治疗以下疾病的唯一方法 这种令人烦恼的疾病。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。各种证据表明自噬过程中存在进行性功能障碍- 斑块巨噬细胞的溶酶体系统，导致无法降解多余的脂质和细胞毒 积聚在动脉粥样硬化斑块中的物质。因此，对降解物重新编程的尝试 巨噬细胞的能力可能是一个富有成效的治疗领域。我们与TFEB的合作，主要 调节自噬-溶酶体生物发生的转录因子表明，在 巨噬细胞可减少小鼠的动脉粥样硬化。我们还发现了一种监管机制 涉及两种关键营养素(氨基酸和胆固醇)和mTORC1，它有效地抑制TFEB和 巨噬细胞中的自噬-溶酶体系统。这增加了靶向营养介导的前景 MTORC1激活可作为一种新的治疗策略。在具体目标1中，我们将评估 动脉粥样硬化中的靶向氨基酸-mTORC1-自噬/溶酶体信号。在具体目标2中，我们将 关注胆固醇-mTORC1-自噬/溶酶体信号通路作为潜在的动脉粥样硬化保护作用 测量。最后，我们了解到许多作为TFEB靶点的自噬-溶酶体基因 在动脉粥样硬化斑块消退的巨噬细胞中显著上调。在具体目标3中，我们将使用 我们的TFEB过度表达小鼠模型，以确定是否利用自噬-溶酶体系统也可以 被用来促进动脉粥样硬化的消退。总体而言，这项提议将检验以下假设： 巨噬细胞mTORC1-自噬/溶酶体途径是治疗动脉粥样硬化的新途径。

Project Summary and 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 reductions in hyperlipidemia and hypertension constitute the only treatments available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that provide mechanistic insight. Various lines of evidence demonstrate a progressive dysfunction in the autophagy- lysosome system of plaque macrophages, leading to an inability to degrade excess lipids and cytotoxic materials accumulating in the atherosclerotic plaque. Thus, 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 this pathway in macrophages leads to reductions in atherosclerosis of mice. We have also uncovered a regulatory mechanism involving two key nutrients (amino acids and cholesterol) and mTORC1 which potently suppresses TFEB and the autophagy-lysosome system in macrophages. This raises the prospect that targeting nutrient-mediated mTORC1 activation can be a novel therapeutic strategy. In specific aim 1, we will evaluate the utility of targeting amino acid-mTORC1-autophagy/lysosomal signaling in atherosclerosis. In specific aim 2, we will focus on the cholesterol-mTORC1-autophagy/lysosomal signaling pathway as a potential atheroprotective measure. Finally, we have learned that many autophagy-lysosome genes which are TFEB targets are prominently upregulated in macrophages of regressing atherosclerotic plaques. In specific aim 3, we will use our TFEB overexpressing mouse model to determine if harnessing the autophagy-lysosome system can also be leveraged to promote atheroregression. Overall, this proposal will test the hypothesis that targeting the macrophage mTORC1-autophagy/lysosomal pathway is a novel approach to treat atherosclerosis.