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

项目概要和摘要 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 诸如降低高脂血症和高血压的改变构成了唯一可用的治疗方法。 这种令人烦恼的疾病。因此，有一个积极的努力，以确定罪魁祸首细胞过程，提供 机械的洞察力各种各样的证据表明自噬过程中的进行性功能障碍- 噬斑巨噬细胞的溶酶体系统，导致不能降解过量的脂质和细胞毒性 在动脉粥样硬化斑块中积聚的物质。因此，试图重新编程降解的 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， 调节自噬-溶酶体生物发生的转录因子，表明增强这一途径， 巨噬细胞导致小鼠动脉粥样硬化的减少。我们还发现了一个监管机制， 涉及两种关键营养素（氨基酸和胆固醇）和mTORC 1，其有效抑制TFEB， 巨噬细胞中的自噬-溶酶体系统。这提出了靶向营养介导前景 mTORC 1激活可能是一种新的治疗策略。在具体目标1中，我们将评估 靶向动脉粥样硬化中的氨基酸-mTORC 1-自噬/溶酶体信号传导。具体目标2： 关注胆固醇-mTORC 1-自噬/溶酶体信号通路作为潜在的动脉粥样硬化保护剂 measure.最后，我们已经了解到，许多自噬溶酶体基因是TFEB的靶点， 在消退的动脉粥样硬化斑块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过表达小鼠模型，以确定利用自噬-溶酶体系统是否也可以 促进动脉粥样硬化消退。总的来说，这一提议将检验这样一个假设， 巨噬细胞mTORC 1-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.