# Clearance of macrophage p62-enriched protein aggregates as a therapy for Atherosclerosis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $2

## Abstract

Project Summary / 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 weight loss, reductions in hyperlipidemia and hypertension constitute the only preventive
strategy available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes
that provide mechanistic insight. Recent work by us and others has renewed interest in the role of the
autophagy-lysosomal system in atherosclerosis. 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
its function in macrophages leads to reductions in atherosclerosis. A critical TFEB target is the autophagy
chaperone p62/SQSTM1 which mediates the removal of cytotoxic protein aggregates. Our work has shown
that clearance of the p62-enriched cargo in macrophages is a novel therapeutic strategy. In specific aim 1, we
will determine the predominant p62-dependent autophagic processes in macrophages that underlie TFEB-
mediated atheroprotection. In specific aim 2, we explore the potential atheroprotective benefits of HSP104, a
novel disaggregase system mostly studied in simple organisms. This approach will be complementary to the
autophagy studies since it is a completely autophagy-independent mechanism of clearing macrophage protein
aggregates. Overall, this proposal will test the hypothesis that harnessing the macrophage degradative
response to clear protein aggregates can be a novel approach to treat atherosclerosis.

## Key facts

- **NIH application ID:** 10428518
- **Project number:** 5R01HL125838-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Babak Razani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2
- **Award type:** 5
- **Project period:** 2014-11-04 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428518

## Citation

> US National Institutes of Health, RePORTER application 10428518, Clearance of macrophage p62-enriched protein aggregates as a therapy for Atherosclerosis (5R01HL125838-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428518. Licensed CC0.

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