# Identifying and protecting alcohol-sensitive epigenetic changes in congenital heart disease

> **NIH NIH K08** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $193,063

## Abstract

This proposal describes a five-year mentored research and training plan that will facilitate the
development of Dr. Stephanie Ford, MD as an independent investigator in the pathogenesis of congenital heart
disease. Building upon Dr. Ford’s background as a clinical neonatologist and a basic scientist, she will attain
expertise in design of mouse studies, RNA-FISH, and epigenetic mechanisms. She will gain skills through
structured mentorship, hands-on laboratory experiences, didactic teaching, and formal classwork at Case
Western Reserve University, FAES at the NIH, and Jackson Laboratories. Dr. Michael Jenkins, a pioneer in
cardiac optical imaging, and Dr. Cynthia Bearer, an expert in prenatal alcohol exposure models, will provide
their expertise and mentorship skills to this project, fostering Dr. Ford’s transition to research independence.
 An estimated 2.4-4.8% of newborns in the U.S. have fetal alcohol spectrum disorders (FASDs), caused by
prenatal alcohol exposure (PAE). PAE induced Congenital Heart Diseases (CHDs) have not been studied as
intensively as other FASD outcomes despite their high prevalence rate (40%). The CHDs associated with
FASDs, mostly valvuloseptal and outflow tract defects, are life-threatening and impact growth and health. PAE
is known to affect methylation and one-carbon metabolism. Normal one-carbon metabolism and its resulting
methylation of DNA is crucial for the correct expression of genes. Comparative genomics studies have revealed
that there is strong epigenetic conservation across vertebrate species including mice and avians, particularly the
hyper-and hypo-methylated DNA sequences of critical genes. We will investigate the PAE-induced changes at
times critical to heart development (endocardial cushion and 4 chamber development) in mouse and avian
embryonic hearts. All hearts will be imaged with optical coherence tomography to rapidly determine their
phenotype. DNA methylation changes will be determined with a combination of methyl-ATAC-seqand bisulfite
sequencing. DNA methylation will be compared in both species, as conserved changes in two species are more
likely to be relevant to human PAE-induced defects. RNA-FISH will be used to confirm gene expression changes,
which will allow us to pinpoint where within the 3D heart, such as the forming valves, gene expression is changing.
 We will then explore the use of choline and glutathione to prevent the effects of PAE. Choline and
glutathione are known to promote methylation in one-carbon metabolism. Choline has been shown in human
studies to prevent early neurologic effects of PAE. We have shown in an avian model that glutathione prevents
the CHDs and abnormal DNA methylation seen after PAE. We will use both avian and mouse models to
determine the effects of alcohol + choline or glutathione on cardiac structure, DNA methylation, and gene
expression. We hypothesize that by maintaining normal methylation, and therefore DNA
expression, our chosen compounds will prevent...

## Key facts

- **NIH application ID:** 10301817
- **Project number:** 1K08AA028845-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Stephanie Marie Ford
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,063
- **Award type:** 1
- **Project period:** 2021-09-10 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301817

## Citation

> US National Institutes of Health, RePORTER application 10301817, Identifying and protecting alcohol-sensitive epigenetic changes in congenital heart disease (1K08AA028845-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10301817. Licensed CC0.

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