# Oxidative Response Networks in Chagasic Cardiomyopathy

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $479,382

## Abstract

ABSTRACT
 Chagas disease, caused by Trypanosoma cruzi, represents the third greatest tropical disease burden. CD
affects >7 million people, causes >17000 deaths, and costs ~$8.0 billion per year in health care costs and lost
productivity. Infected individuals present oxidative and inflammatory stress, ventricular fibrosis and dilatation,
and eventually develop congestive heart failure.
 In this project, we propose to examine a novel role of poly (ADP-ribose) polymerase 1 (PARP1) in
chagasic pathology and offer an innovative potential therapy. Briefly, we believe that PARP1 cross-talk with
mitochondrial DNA polymerase G (POLG) effects the mtDNA integrity, leading to a decline in respiratory chain
efficiency and increase in mitochondrial reactive oxygen species (ROS) production in cardiomyocytes and
chagasic heart. Moreover, phagocytosis of ROS-induced cell debris along with PARP1-dependent metabolic
switch in macrophages signals activation and proliferation of proinflammatory macrophages. We will employ
innovative, fluorescence-based, assays that measure multiple functional responses in the same sample to test
our hypothesis in two specific aims.
 In aim 1, our objectives are to demonstrate that PARP1 activation increases the risk of clinical heart
disease in infected patients, dissect how PARP1 interferes with mtDNA replisome with increasing severity of
heart disease, and test that targeted delivery of PARP1 inhibitors to mitochondria preserves mitochondrial
health and LV function in Chagas disease.
 In aim 2, our objectives are to test that extracellular vesicles (EV) produced due to ROS/PARP1-induced
cellular injury carry the immune signature of chronic Chagas disease. We will demonstrate that EVs, in a
disease stage-specific manner, engage intracellular innate immune receptors of macrophages, and
macrophage expression of PARP1 provides metabolic signal for glycolytic switch and proinflammatory mφ
activation. Importantly, we will test that controlling PARP1 activation is beneficial in silencing the tissue-
destructive, inflammatory phenotype of chagasic patients’ macrophages.
 We believe the innovation lies in the idea of demonstrating how a DNA repair protein can disturb
mitochondrial function and intensify inflammation. We will provide mechanistic insights into how these
processes are linked and offer a novel therapy for preserving metabolic homeostasis and LV function in
Chagas disease cases.

## Key facts

- **NIH application ID:** 9991608
- **Project number:** 5R01AI136031-08
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Nisha Jain Garg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $479,382
- **Award type:** 5
- **Project period:** 2009-01-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991608

## Citation

> US National Institutes of Health, RePORTER application 9991608, Oxidative Response Networks in Chagasic Cardiomyopathy (5R01AI136031-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991608. Licensed CC0.

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