# Intracellular immunity, cytosolic DNA sensing by cyclic GAMP synthase, and macrophages in ischemic injury and cardiac remodeling

> **NIH VA I01** · VA NORTH TEXAS HEALTH CARE SYSTEM · 2021 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
The recent CANTOS Trial has proved that anti-infammation therapy targeting the interleukin-1β lowers the
incidence of cardiovascular events. However, we lack therapies that can limit the inflammatory injury triggered
by acute ischemia, even though it clearly links to worse clinical outcomes. A critical gap of knowledge in
understanding danger recognition, especially intracellular danger recognition, plays a significant role, because
detecting danger dictates the scope of inflammation. Our long-term goal is to develop immune modulators that
modify danger recognition to contain inflammation-mediated injury. The overall objective of this proposal is to
determine how DNA and its cytosolic receptor the cyclic GAMP synthase (cGAS) propagate injury triggered by
ischemia. The damaged myocardium is enriched with both mitochondrial (thousands of copies per
cardiomyocyte) and nuclear DNA. The large amount of DNA poses a serious threat to myocardial repair when
macrophages, the professional phagocytes, detect it and respond with the robust inflammatory responses
intended to get rid of pathogens from the evolutionary standpoint. The central hypothesis of this project is that
recognition of DNA by cGAS sustains the inflammatory macrophages via activation of the type I interferon (IFN)
pathway that promotes AIM2 (absent in melanoma 2) inflammasone; as a result, cGAS is crucial in ischemia-induced
remodeling. This hypothesis has been formulated on the preliminary data and the recently published work from the
applicants’ laboratory. The rationale for the proposed research is that understanding the intracellular immunity in
ischemic-triggered inflammation has the potential to discover effective ways of limiting inflammation-related injury.
Guided by strong preliminary data, this hypothesis will be tested by pursuing the following specific aims: 1)
Determine that cGAS activation in macrophages drives pathological remodeling and HF; 2) Determine
that cGAS-mediated signaling activates the AIM2 inflammasome pathway. cGAS activates type 1 interferon-
mediated signaling that governs the expression of the guanylate binding proteins (GBPs). GBPs destabilize
the phagosome and cause the release of DNA into the cytosol and triggers AIM2 inflammasome activation; 3)
Identify effective approaches for inhibition of the cGAS pathway to reduce remodeling and HF after ischemic
injury. Aim 1 will be addressed using a cGASf/f mouse line to determine macrophage as the responsible cell type.
Under the second aim, the cGAS-dependent AIM2 inflammasone activation and the essential roles of GBPs
will be examined using loss or gain of function experiments with in vitro and in vivo models. Aim 3 will test
potential protection from immune modulators that inhibit the cGAS-mediated signaling, including two clinically
available agents. The study is conceptually novel by targeting DNA and its cytosolic sensing system,
traditionally viewed as a viral response pathway, in t...

## Key facts

- **NIH application ID:** 10105183
- **Project number:** 5I01BX004562-02
- **Recipient organization:** VA NORTH TEXAS HEALTH CARE SYSTEM
- **Principal Investigator:** Dian Cao
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105183

## Citation

> US National Institutes of Health, RePORTER application 10105183, Intracellular immunity, cytosolic DNA sensing by cyclic GAMP synthase, and macrophages in ischemic injury and cardiac remodeling (5I01BX004562-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10105183. Licensed CC0.

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