# Epigenetic Mechanisms Underlying Maternal Diabetes Associated Cardiac Malformations

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2020 · $380,000

## Abstract

Abstract
 Congenital heart defects constitute a significant pediatric and adult health problem. They not
only represent the leading non-infectious cause of death in infants, but the growing number of adult
survivors also suffer significant morbidity. Numerous genetic contributors have been identified to
cause congenital heart defects ranging from chromosome abnormalities to single gene defects.
Congenital heart disease-causing genes have been well-studied using animal models and the
molecular pathways regulating normal cardiac morphogenesis are being increasingly defined.
Environmental factors are known to increase the incidence of congenital heart defects. A significant
knowledge gap exists in our understanding of the mechanisms by which environmental factors affect
the molecular pathways regulating heart development to increase the risk of congenital heart disease.
 Maternal diabetes is a well-established and increasingly prevalent environmental risk factor for
congenital heart disease. We recently described a novel gene-environment interaction between
maternal hyperglycemia and Notch1 signaling that increased the risk of congenital heart defects in
animal models. Our studies suggested that alterations in the epigenetic regulation of the nitric oxide
and Notch1 signaling pathways were responsible for this interaction. Our long-term objective is to
define the molecular and cellular pathways underlying this interaction and define a paradigm by which
gene-environment interactions occur to cause congenital heart defects. The overall hypothesis of this
research is that maternal diabetes-associated congenital heart disease occurs when maternal
hyperglycemia-induced reactive oxygen species disrupts normal cardiac morphogenesis by
epigenetic mechanisms and will be addressed in the following specific aims: Aim 1. To determine the
cell-specific and temporal mechanisms by which hyperglycemia-associated oxidative stress mediates
reduced chromatin accessibility at the Nos3 locus to cause congenital heart disease. Aim 2. To define
the mechanism by which nitric oxide regulates the expression of the epigenetic Notch1 regulator,
Jarid2. Aim 3. To determine if alterations in chromatin regulatory genes that occur with hyperglycemia
contribute to maternal diabetes-associated congenital heart defects. Elucidating the molecular basis
for the epidemiologic association between diabetes and cardiac malformations is required in order to
devise novel preventive strategies for diabetes-associated congenital heart disease and potentially
identify at risk individuals. Successful completion of the proposed studies will result in a significant
advancement in our molecular understanding of the mechanisms by which gene-environment
interactions contribute to congenital heart defect occurrence.

## Key facts

- **NIH application ID:** 9997990
- **Project number:** 5R01HL144009-02
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Vidu Garg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,000
- **Award type:** 5
- **Project period:** 2019-08-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997990

## Citation

> US National Institutes of Health, RePORTER application 9997990, Epigenetic Mechanisms Underlying Maternal Diabetes Associated Cardiac Malformations (5R01HL144009-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9997990. Licensed CC0.

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