# Cardiogenesis: Molecular Mechanisms

> **NIH NIH R01** · J. DAVID GLADSTONE INSTITUTES · 2021 · $661,959

## Abstract

PROJECT SUMMARY/ABSTRACT
Congenital heart disease (CHD), the most common human birth defect, is the result of abnormal development
of discrete sub-types of cardiogenic cells during early embryogenesis. The recent ability to analyze the
transcriptomes of tens of thousands of individual cells has made it tractable to discern the consequences of
genetic mutation on small subsets of cells that could lead to CHD. Nearly 30% of all CHD involve the
developing valvuloseptal region, which arise from some of the more rare cell types in the heart. Secreted
myocardial signals in valve-forming regions are received by the endocardium and stimulate endocardial to
mesenchymal transformation (EMT) resulting in cells that invade the extracellular matrix and form the
primordia of future valves and contribute to cardiac septation. We performed single cell RNA sequencing
(scRNAseq) of over 100,000 cells from mouse hearts between E7.75 – E13.5 before and after EMT is
occurring. We have, for the first time, defined the transcriptomes of specific individual cell types that are
involved in valvuloseptal formation, revealing novel markers and pathways involved in this process. We have
begun to define the pathways disrupted in the relevant cell types in a mouse model of atrioventricular septal
defects (AVSD) caused by heterozygosity for Gata4 and Tbx5, and human iPSCs heterozygous for a GATA4
missense mutation from a patient with AVSD. AVSDs are most commonly seen in the setting of Trisomy 21
(Down Syndrome), yet the cause remains unknown. We propose to use the “atlas” of single cell gene
expression during valvuloseptal development and human iPSCs to test the hypothesis that the genetic
pathways disrupted in specific cardiac cells in Down Syndrome overlap with those involving known regulators
of atrioventricular septation and EMT, and that this knowledge will reveal the gene(s) involved in cardiac
defects associated with Down Syndrome. We approach this through the following specific aims: 1) To
determine cell types and gene networks involved in AVSD by comparing and contrasting temporal single cell
gene expression and epigenetic networks disrupted in atrioventricular canal myocardium, endocardial cells,
and valve mesenchymal cells in mouse models of AVSD; 2) To determine cell types and gene networks
dysregulated in human AVSD disease models by comparing and contrasting single cell gene expression and
epigenetic alterations in human iPSC-derived myocardial and endothelial cells from Trisomy 21 patients and
from GATA4/TBX5 mutant cells; and 3) To determine which gene(s) on human chromosome 21 are sufficient
to cause gene dysregulation observed in valvuloseptal defects and phenotypic changes in mice. The
combination of mouse models, human iPSC models, and single cell genomics will reveal the cell types and
mechanisms associated with valvuloseptal defects common to Down Syndrome.

## Key facts

- **NIH application ID:** 10242803
- **Project number:** 5R01HL057181-26
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** DEEPAK SRIVASTAVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $661,959
- **Award type:** 5
- **Project period:** 1997-01-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242803

## Citation

> US National Institutes of Health, RePORTER application 10242803, Cardiogenesis: Molecular Mechanisms (5R01HL057181-26). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242803. Licensed CC0.

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