# GasderminD regulation of Acute Lung Injury

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $566,763

## Abstract

Abstract:
 The loss of lung endothelial barrier function and endothelial cell (EC) death is a primary pathogenic feature
of acute respiratory distress syndrome (ARDS). Although it appears that fundamental immune cell processes
are at the core of ARDS-mediated vascular injury and dysfunction, the actual mechanism of endothelial cell
death regulated by immune cells remains largely unknown. As a result there are currently no effective
pharmacologic therapies. In order to develop more effective therapeutic strategies, it is therefore necessary to
understand the precise mechanisms that link immune cell function to vascular dysfunction.
 This proposal focuses on a new molecular paradigm whereby immune cells (monocytes) drive endothelial
cell death. Our extensive supportive data have lead us to formulate the overarching hypothesis that links lung
endothelial injury during ARDS to the pyroptotic function of monocyte/macrophage derived GasderminD
(GsdmD) encapsulated in circulating microparticles(MP) in association with purinergic receptor, P2X7. To
determine the specifics of this novel pathway, we propose the following specific aims. In Aim1, we will
delineate the role of monocyte derived GasderminD in mediating endothelial pyroptosis in the mechanism of
ALI. We will use available murine model along with in vitro and ex vivo model of ARDS patients to study
GsdmD mediated endothelial injury. In Aim2, we will determine the regulation of MP encapsulated GsdmD’s
cytopathic function by monocytes. We will study the mechanism how phosphorylation of GasderminD regulates
its cytopathic behavior and vulnerability to ubiquitin-mediated degradation. Finally, in Aim3, we will delineate
the role of P2X7 in the mechanism of MP GsdmD mediated endothelial cell death. We will study the
mechanisms of extracellular MP-associated GsdmD engagement to target cells mediated by the functional
purinergic receptor P2X7.
 These studies will be the first to elucidate the injurious behavior of extracellular GsdmD in coordination with
the purinergic receptor, P2X7 encapsulated in MPs, which may play a central role in lung injury. Execution of
these studies will lay the foundation for a significant mechanistic advance regarding the cellular interplay
between immune cells and endothelia that may provide opportunities for devising novel therapeutic targets that
lessen the severity of lung vascular injury.

## Key facts

- **NIH application ID:** 10868705
- **Project number:** 5R01HL160947-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Anasuya Sarkar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $566,763
- **Award type:** 5
- **Project period:** 2022-08-05 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868705

## Citation

> US National Institutes of Health, RePORTER application 10868705, GasderminD regulation of Acute Lung Injury (5R01HL160947-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10868705. Licensed CC0.

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