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

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2020 · —

## 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 treatment strategy
available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that
provide mechanistic insight. Reports of the pro-atherogenic phenotype of mice with a macrophage-specific
autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis.
Lysosomes have the unique role of processing both exogenous material such as excess atherogenic lipids and
endogenous cargo that includes dysfunctional proteins and organelles. Indeed, this is a primary mechanism
by which macrophages can degrade excess lipids and cytotoxic materials present in the atherosclerotic
plaque. Various lines of evidence demonstrate a progressive dysfunction in the autophagy-lysosome system of
plaque macrophages suggesting that 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 TFEB function in macrophages leads to reductions in
atherosclerosis of mice. In an attempt to harness this pathway therapeutically, we have uncovered a safe and
natural sugar called trehalose, able to induce TFEB and autophagy-lysosome biogenesis in macrophages and
recapitulate the atheroprotective properties. This raises the prospect of this sugar as a novel and practical
therapy. In specific aim 1, we will dissect the mechanisms linking trehalose to macrophage autophagy-
lysosomal biogenesis. In specific aim 2, we will determine the predominant autophagic processes in
macrophages that underlie trehalose’s ability to reduce atherosclerosis. A major impediment to the therapeutic
use of trehalose is degradation by the enzyme trehalase, present in higher organisms including mammals. In
specific aim 3, genetic and pharmacological techniques of inhibiting trehalase will be used to determine if
trehalose’s effects can be synergized. This proposal will test the hypothesis that trehalose can harness
macrophage autophagy-lysosomal biogenesis to treat atherosclerosis.

## Key facts

- **NIH application ID:** 9861193
- **Project number:** 5I01BX003415-03
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Babak Razani
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861193

## Citation

> US National Institutes of Health, RePORTER application 9861193, Harnessing the Autophagy-Lysosomal Biogenesis Response in Macrophages to Treat Atherosclerosis (5I01BX003415-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9861193. Licensed CC0.

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