# Genetic Control of Cardiac Development: Congenital Heart Disease Gene Discovery in Drosophila

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2024 · $822,148

## Abstract

PROJECT SUMMARY
 Congenital heart defects/diseases (CHDs) are the most common developmental anomalies and are the
leading non-infectious causes of mortality in newborns, underscoring the importance of studying the underlying
causes. The main genetic contributors are known for only 10-15% of CHD patients, thus hundreds more have
yet to be discovered. It is our goal to systematically elucidate the genetic basis of CHDs. This is particularly
challenging in mammalian models due to their genetic complexity and the often oligogenic nature of CHDs. We
and others have originally defined a first set of ‘cardiogenic’ genes in Drosophila that specify the heart (e.g.
tinman/Nkx2-5). These insights served as a prototype for elucidating fundamentally conserved mechanisms of
cardiac development throughout the animal kingdom (~80% of human disease genes have fly orthologs). Over
the past grant cycle, our lab made considerable progress in elucidating the molecular-genetic basis of heart
development, establishment of heart function and importantly of CHD gene discovery and combinatorial
assessment of candidate gene functions. With our new high-throughput multidisciplinary platforms, we have the
unprecedented, but much needed ability to functionally and in-depth evaluate a multitude of candidate genes
from whole genome sequencing (WGS) data, also patient-specifically, to begin to create comprehensive
cardiogenic gene regulatory networks (GRNs) in health and disease.
 In this application, we propose to create and functionally test in high-throughput comprehensive GRNs
of cardiogenesis, initially based on single cell gene expression profiles (by scRNAseq) of cardioblasts (CBs)
sorted from wildtype Drosophila embryos, as well as from mutant hearts for core cardiogenic transcription factors
(cTFs), such as tinman. In a complementary approach, we will evaluate patient-specific sets of human CHD
gene candidates, identified and bioinformatically prioritized from WGS by our collaborators, by testing them in
our in vivo Drosophila heart model, in human iPSC-derived cardiomyocytes (hiPSC-CM), with validation in
zebrafish, followed by integration in the emerging GRNs. In Aim 1, we propose to conduct genetic interaction
studies of cTFs with prioritized gene sets based on scRNAseq profiles of FACS-sorted CBs from wildtype vs.
mutant Drosophila embryos, with the goal to construct and refine cardiogenic GRNs. In Aim 2, we propose to
identify, test and network new, potentially causal CHD genes and their mechanisms, focusing on ribosomal
protein gene RpL13 and mitochondrial MICOS complex genes. It is our goal to harness the power of the
(evolutionarily conserved) Drosophila heart (with validation in hiPSC-CM and zebrafish) for new gene/pathway
discovery to generate integrated GRNs for CHD, as a basis for the development of diagnostic tools and
therapeutic interventions.

## Key facts

- **NIH application ID:** 10884303
- **Project number:** 5R01HL054732-27
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** ROLF BODMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $822,148
- **Award type:** 5
- **Project period:** 1995-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884303

## Citation

> US National Institutes of Health, RePORTER application 10884303, Genetic Control of Cardiac Development: Congenital Heart Disease Gene Discovery in Drosophila (5R01HL054732-27). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10884303. Licensed CC0.

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