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

项目摘要及摘要

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.