# Developmental mechanisms of human congenital heart disease

> **NIH NIH P01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $1,497,819

## Abstract

ABSTRACT
This P01 renewal application is in response to RFA, HD-16-009 from the NICHD institute of NIH to
determine developmental mechanisms of structural birth defects. This renewal will continue on the current
theme to identify genes and mechanisms responsible for congenital heart disease. The class of congenital
heart disease that is the focus of the P01 is termed, conotruncal and related aortic arch defects, referred to
as CTRDs. Studies of animal models indicate that there are similar developmental mechanisms disrupted
during embryogenesis causing conotruncal heart defects and/or aortic arch anomalies. In particular, the
cardiac outflow tract and aortic arch derive from shared precursor cell populations from within the embryonic
pharyngeal apparatus. The molecular basis of CTRDs is extremely complex, based upon genetic studies of
non-syndromic CTRDs (NS-CTRDs; Project 2), in which the full spectrum of genetic variation is likely
responsible. In order to tackle this complex birth defect, this program renewal consists of three
interdependent projects. In Project 1, we will identify genetic modifiers of CTRDs in 22q11.2 deletion
syndrome (22q11.2DS; aka DiGeorge syndrome velo-cardio-facial syndrome). The idea is that the deletion
itself serves to sensitize the genome for further genetic insults that may shed light onto the mechanisms of
disease in more heterogeneous NS-CTRDs. We have positive findings towards this goal in the discoveries
of the SLC2A3 duplication and histone modifier genes in the 22q11.2DS cohort. However, due to the
complexity of the genetics in 22q11-CTRD and NS-CTRD cohorts, as well as limited sample sizes, we have
turned to a focus on the biology of the developing pharyngeal apparatus (including additional emerging
pathways) to examine gene-sets rather than taking agnostic approaches. The Bio-analytics Core will
provide the biostatistics and bioinformatics oversight. In Project 2, we will examine common and rare DNA
variants in gene-sets for severe CTRDs, as well as understand the genetic architecture of severe versus
mild CTRDs, specifically, isolated aortic arch anomalies. In Project 3, we will use mouse models of
22q11.2DS, where we focus on two particular genes in the deleted region, Tbx1, encoding a T-box
transcription factor and Crkl, encoding an adaptor for intracellular signaling, in forming the aortic arch.
Secondly, we will identify the transcriptomes from the microdissected pharyngeal apparatus from these
models and others (Lgdel/+) to generate an interactive gene network, termed the PA-INet to be used in
Projects 1 and 2 and organized in the Bio-analytic Core. Finally, we will perform functional analysis of top
genes and loci, first bioinformatically, but then in cell culture and finally in mouse models. We believe our
strategy, focusing on 22q11.2DS and developmental mechanisms, will make it possible to gain unique
inroads into this important human structural birth defect.

## Key facts

- **NIH application ID:** 9938641
- **Project number:** 5P01HD070454-12
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** BERNICE E MORROW
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,497,819
- **Award type:** 5
- **Project period:** 2011-09-24 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938641

## Citation

> US National Institutes of Health, RePORTER application 9938641, Developmental mechanisms of human congenital heart disease (5P01HD070454-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9938641. Licensed CC0.

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