# Role of cGAS-STING in cardiomyocyte cell cycle regulation

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $358,611

## Abstract

Project Summary
Heart failure progression is a complex biological process that is precipitated by the maladaptive
myocardial response to injury, compounded by failure of the adult heart to replace lost or damaged
cardiomyocytes. Our lab has previously outlined the regenerative capacity of the newborn
mammalian heart and outlined several mechanisms that regulate this process. Specifically, we
demonstrate that the endogenous regenerative capacity of the newborn heart is mediated by
proliferation of preexisting cardiomyocytes and is lost when cardiomyocytes exit cell cycle within
a few days after birth. We described several fundamental mechanisms that regulate cell cycle exit
of cardiomyocytes, including spontaneous DNA damage that occurs as a result of increased
mitochondrial oxidative phosphorylation. We also demonstrated that DNA damage activates DNA
damage response (DDR), which mediates cell cycle arrest of cardiomyocytes whereby inhibitors
of DDR prolong the window of cardiomyocyte proliferation. We also examined other potential
consequences of DNA damage, namely the formation of micronuclei, which is free cytoplasmic
DNA that often results from DNA damage during mitosis. Our preliminary results indicate that the
micronuclei are detected in cardiomyocytes at the time of cell cycle arrest. We also found that the
DNA sensing pathway cGAS-STING is induced in the postnatal heart within the same timeframe.
Intriguingly, inhibiting cGAS results in prolongation of the postnatal window of cardiomyocyte
proliferation. Therefore, this project will focus on the role of intra-cardiomyocyte cGAS-STING in
regulation of heart regeneration. We will examine the mechanism of activation of cGAS-STING in
cardiomyocytes, the effect of inhibiting cGAS-STING on cardiomyocyte proliferation, and the
downstream mechanisms that regulate cGAS function in cardiomyocytes.

## Key facts

- **NIH application ID:** 10821364
- **Project number:** 5P01HL160488-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Hesham Sadek
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $358,611
- **Award type:** 5
- **Project period:** 2023-04-05 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821364

## Citation

> US National Institutes of Health, RePORTER application 10821364, Role of cGAS-STING in cardiomyocyte cell cycle regulation (5P01HL160488-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10821364. Licensed CC0.

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