# The Role of Gasdermin-D/Interleukin-1 Nexus in Atrial Arrhythmogenesis

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $650,578

## Abstract

PROJECT SUMMARY
Atrial fibrillation (AF) is the most frequent arrhythmia. Enhanced activation of ‘NACHT, LRR and PYD domains-
containing protein 3’ (NLRP3) inflammasome plays a causal role in promoting proarrhythmic events associated
with AF development. Activation of NLRP3 inflammasome produces two major effectors: interleukin (IL)-1b and
cleaved (active) N-terminal gasdermin-D (GSDMDNT). The precise functions of IL-1b and GSDMDNT in
cardiomyocytes and atrial arrhythmogenesis are largely unknown. Our preliminary data revealed that
cardiomyocyte-specific knockdown of IL-1b receptor type-1 (IL-1R1) attenuates susceptibility to AF of mice with
cardiomyocyte NLRP3 gain-of-function. Meanwhile, atrial specific overexpression of GSDMDNT in mice
(aGSDMDNT) also creates an arrhythmic substrate for AF development. Because the main function of GSDMDNT
is to form plasma membrane pores allowing the cell release of IL-1b and IL-1b protein is upregulated in
aGSDMDNT mice, we hypothesized that this GSDMDNT/IL-1b nexus creates a substrate for AF by promoting a
feedforward loop of NLRP3-inflammasome activation. Using mouse and human atrial systems we propose to 1)
elucidate the role of IL-1b signaling in cardiomyocytes and atrial arrhythmogenesis, 2) establish the causative
role and the functions of cardiomyocyte GSDMDNT in atrial arrhythmogenesis, and 3) establish and validate
GSDMDNT/IL-1b nexus as the driver of a feedforward loop of NLRP3-inflammasome activation in atrial
arrhythmogenesis. The outcome of these studies will provide a proof-of-concept for atrial specific targeting of IL-
1b signaling in AF patients and uncover novel and unique functions of IL-1b and GSDMDNT in atrial
cardiomyocytes and their specific contributions to AF development.

## Key facts

- **NIH application ID:** 10749878
- **Project number:** 5R01HL136389-07
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Na Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $650,578
- **Award type:** 5
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10749878

## Citation

> US National Institutes of Health, RePORTER application 10749878, The Role of Gasdermin-D/Interleukin-1 Nexus in Atrial Arrhythmogenesis (5R01HL136389-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10749878. Licensed CC0.

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