# Phosphatidylinositol Metabolism and Trafficking in Atherosclerosis and Inflammation

> **NIH NIH R01** · CLEVELAND STATE UNIVERSITY · 2021 · $397,334

## Abstract

Project Summary
PIP2 is a minor phospholipid (PL) and plays a critical role in a variety of cellular functions but
the role of PIP2 in atherosclerosis and Nlrp3/ IL-1 inflammasome pathway is not well
characterized. I have previously shown that ABCA1 functions as a phosphatidylinositol 4, 5-
bisphosphate (PIP2) floppase, transporting PIP2 from the inner to the outer leaflet of the plasma
membrane. ABCA1, a cellular cholesterol efflux transporter, plays a major role in preventing
atherosclerosis and inflammation by effluxing excess lipids/cholesterol from cells and by
blocking pro-inflammatory pathways. Human patients with mutations in Abca1 suffer from
premature atherosclerosis and macrophage-specific knockout of ABCA1/G1 in Ldlr KO mice
promotes atherosclerosis and plaque inflammation. The role of pro-inflammatory Nlrp3/IL-
1pathway in atherosclerosis was highlighted by CANTOS trial showing that anti-IL-1β therapy
met the primary trial endpoint, a reduction in a composite of heart attack, stroke and
cardiovascular death. Recent studies have shown that Gasdermin D (GsdmD), a newly
discovered substrate of the inflammasome, binds to PIP2 on the plasma membrane and
oligomerize, generating pores for releasing mature IL-1. The proposed studies will unravel the
novel roles of PIP2 in these pathways and may open new windows for therapeutic intervention
to prevent cardiovascular disease (CVD). This proposal will further establish PIP2 as a major
regulator of cellular cholesterol efflux and identify the PIP2 flippases (P4-type ATPases that
transport PIP2 from the outer to the inner leaflet of the plasma membrane) that in turn regulate
cholesterol efflux and inflammation. The proposal will identify the role of GsdmD in
atherosclerosis, reverse cholesterol transport (RCT), and in reversing the negative effects of
inflammation on RCT. The three main goals of this proposal are; 1) to establish PIP2 as a
major cellular cholesterol efflux regulator, 2) to identify and characterize the PIP2 flippase and
determine the role of P4-type ATPases in cholesterol efflux and inflammation, and 3) to
determine the role of Gasdermin D in atherosclerosis and RCT.

## Key facts

- **NIH application ID:** 10131256
- **Project number:** 5R01HL148158-03
- **Recipient organization:** CLEVELAND STATE UNIVERSITY
- **Principal Investigator:** Kailash Gulshan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,334
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131256

## Citation

> US National Institutes of Health, RePORTER application 10131256, Phosphatidylinositol Metabolism and Trafficking in Atherosclerosis and Inflammation (5R01HL148158-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10131256. Licensed CC0.

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