# Cholesterol efflux, CHIP and inflammasome activation

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $604,538

## Abstract

Project Summary/Abstract
Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality in
the US. Despite the benefits of LDL lowering therapies, there remains a large burden of residual
CVD, related to persistent dyslpidemia and inflammation. Even though CANTOS and colchicine
trials have established the benefit of anti-inflammatory therapies, these approaches were
associated with a significant increase in infectious complications, limiting their clinical application.
This suggests the need for a deeper understanding of the links between dyslipidemia and
atherosclerotic inflammation, leading to more effective targeting of relevant mechanisms and
susceptible populations. This grant has supported studies of the mechanisms linking defective
cholesterol efflux pathways to macrophage and neutrophil inflammatory processes, including
NLRP3 inflammasome activation and neutrophil extracellular trap (NET) formation. We recently
discovered a new pathway linking macrophage cholesterol accumulation (mediated through
defective cholesterol efflux or loading with modified LDL) to ER cholesterol accumulation and
activation of a signaling pathway that leads to deubiquitylation and assembly of the NLRP3
inflammasome. Inhibition of this pathway with the deubiquitinase inhibitor holomycin led to
reduced atherosclerosis and NETosis, suggesting a new approach to reducing inflammasome
activation and atherosclerosis. The same pathway appears to be activated in TET2 clonal
hematopoiesis. The proposed studies will further explore the role of the newly defined pathway
in promoting NLRP3 inflammasome activation and atherosclerosis in hyperlipidemic mice with
defective cholesterol efflux or TET2 clonal hematopoiesis and in human cells containing TET2
mutations. The ability of reconstituted HDL to promote cholesterol efflux and to reverse
inflammasome activation, leading to plaque stabilization, will also be investigated. The proposal
should provide new mechanistic insights into the links between macrophage cholesterol
accumulation and plaque inflammation and will evaluate novel precision therapeutic approaches
to atherosclerosis.

## Key facts

- **NIH application ID:** 10888992
- **Project number:** 5R01HL107653-14
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ALAN richard TALL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $604,538
- **Award type:** 5
- **Project period:** 2011-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888992

## Citation

> US National Institutes of Health, RePORTER application 10888992, Cholesterol efflux, CHIP and inflammasome activation (5R01HL107653-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10888992. Licensed CC0.

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