# Phosphatidylinositol Metabolism and Trafficking in Atherosclerosis and Inflammation

> **NIH NIH R01** · CLEVELAND STATE UNIVERSITY · 2024 · $540,777

## Abstract

Project Summary
Dysfunctional inflammatory immune responses to modified lipids/cholesterol and bacterial components such as
LPS leads to unresolved and chronic inflammation, promoting various metabolic and genetic diseases. One
prime example of chronic inflammatory disease is atherosclerosis, a major cause of cardiovascular disease
(CVD) related mortalities. Despite progress in treatments, CVD still accounts for ~1 out of every 3 deaths in the
USA. Another disease related to dysregulated cholesterol metabolism and unresolved extrahepatic
inflammation is progressive familial intrahepatic cholestasis 1 (PFIC1), where mutations in ATP8b1 (a member
of the type 4 subfamily of P-type ATPases) perturbs the detergent-resistant state of the hepatic canalicular
membrane, leading to hepatic injury. While much is known about the pathophysiology of PFIC1, the underlying
mechanism for how the loss of ATP8b1 leads to compromised integrity of the canalicular membrane is not
clear. A high throughput proteomic analysis suggests that ATP8b1 flippase activity and phosphoinositide
metabolism may be interconnected, but the mechanistic link between ATP8b1 and phosphatidylinositol
metabolism is not clear. Our data provide novel insights into the mechanism that leads to plasma membrane
remodeling in PFIC1 macrophages and hepatocytes by establishing role of ATP8b1 in PIP2 trafficking. We are
proposing cutting-edge methods to unequivocally establish PIP2 flippase activity of ATP8b1, making it the first
known PIP2 flippase from any system. PFIC1 patients often present with extrahepatic inflammatory
manifestations, suggesting role of ATP8b1 in regulating inflammation. Recent studies have highlighted the
major role of pyroptosis executor Gasdermin D (GsdmD), a pore-forming protein, in promoting a variety of
inflammatory diseases. Our data identified ATP8b1 as the first known negative regulator of GsdmD cleavage
and we propose to decipher the mechanism of this effect in human induced pluripotent stem cells (iPSCs) and
mouse models of inflammation. In addition, we will determine the therapeutic efficacy of targeting GsdmD in
reducing atherosclerosis and determine the tissue-specific role of GsdmD in CVD.
Successful completion of these aims will reveal new biology underlying PFIC1 extrahepatic inflammatory
manifestations and GsdmD-induced progression of atherosclerosis. Our data showing GsdmD cleavage to be
the primary mechanism behind increased IL-1β release in ATP8b1-/- monocytes and macrophages may allow
the design of anti-GsdmD therapeutics for treating extrahepatic inflammation in PFIC1. Our data showing the
efficacy of Disulfiram as an anti-atherosclerotic reagent in hyperlipidemic mice provide pre-clinical data for
targeting GsdmD for treating atherosclerosis. Elucidation of tissue-specific role of GsdmD will open up new
fields of investigation and therapeutic interventions for treating atherosclerosis.

## Key facts

- **NIH application ID:** 10878045
- **Project number:** 2R01HL148158-06
- **Recipient organization:** CLEVELAND STATE UNIVERSITY
- **Principal Investigator:** Kailash Gulshan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $540,777
- **Award type:** 2
- **Project period:** 2020-04-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878045

## Citation

> US National Institutes of Health, RePORTER application 10878045, Phosphatidylinositol Metabolism and Trafficking in Atherosclerosis and Inflammation (2R01HL148158-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10878045. Licensed CC0.

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