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

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2022 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10370137
- **Project number:** 2I01BX003415-05A1
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Babak Razani
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2018-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370137

## Citation

> US National Institutes of Health, RePORTER application 10370137, Harnessing the Autophagy-Lysosomal Biogenesis Response in Macrophages to Treat Atherosclerosis (2I01BX003415-05A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10370137. Licensed CC0.

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