Manipulation of leucine uptake, sensing, and metabolism in macrophages as a diagnostic and therapeutic strategy in atherosclerosis

About This Grant

Project Summary / Abstract Despite numerous improvements in treatment and prevention, cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality worldwide. Nutrients such as lipid, particularly derived from the diet, have long been linked to the development and exacerbation of CVD. However, the role of other nutrients such as amino acids in the pathogenesis of CVD has largely remained unexplored. In work spanning the past decade, we have implicated amino acids as key stimuli in pathogenic mTOR signaling in macrophages via a lysosomal nutrient-sensing mechanism. We further identified leucine as the single most important nutrient driving this lysosomal mTOR signaling in atherosclerosis. A significant contributing factor to leucine-mediated signaling is the concomitant increase in a major leucine transporter, SLC7a5/LAT1. Macrophage Slc7a5-deficiency significantly reduces mTOR signaling and plaque size and complexity in atherogenic mice. We have also leveraged the upregulation of leucine transport as a diagnostic approach to imaging atherosclerotic plaques by demonstrating the affinity of a leucine-like PET radiotracer to macrophage-rich areas of lesions. Beyond leucine uptake, we recently discovered that its catabolism is inhibited in plaque macrophages which exacerbates leucine accumulation and mTOR. Overall, we provide multiple promising approaches to modulating leucine-mTOR signaling in macrophages. In this proposal, we will impinge on each of these processes by genetic and pharmacological means in order to test the hypothesis that perturbation of leucine uptake, lysosomal sensing, and metabolism can be effective diagnostic and therapeutic strategies in atherosclerosis. This will be achieved in three distinct aims: 1) to evaluate the diagnostic and therapeutic potential of modulating macrophage leucine uptake in atherosclerosis, 2) to dissect the salient leucine-sensing mechanisms at the lysosome in driving mTOR activation and atherosclerosis, and 3) to evaluate the therapeutic potential of enhancing macrophage leucine catabolism in atherosclerosis. We will use an innovative set of tools including novel PET probes and a diverse array of mouse models to pursue a highly mechanistic evaluation of macrophage leucine-mTOR signaling in CVD.