# Evaluation of Hedgehog signaling-dependent heart development in a mouse model of Down Syndrome

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2023 · $445,985

## Abstract

The fundamental question for the field of Down Syndrome (DS) basic research is how an extra
copy of human chromosome 21 (HSA21) translates into the organ-specific pathologies that are
observed in the DS population. Structural pathologies in DS include congenital heart
malformations, including a 2000-fold increased risk for Atrioventricular Septal Defects (AVSDs).
A mechanistic understanding of DS-specific organogenesis defects is lacking, and specifically,
how Trisomy 21 (T21) causes Congenital Heart Disease is poorly understood. In the parent
award, we have defined Hedgehog (Hh) signaling as an explicit development timer of cardiac
differentiation during mammalian development. Furthermore, there is plentiful evidence that
suggests that T21 causes Hedgehog signaling defects. In this supplement, we propose to
evaluate cardiac progenitors in Tc(HSA21q;MAC)1Yakaz ("TcMAC21"), a new mouse model of
DS with a stably segregating HSA21q-MAC hybrid chromosome that is nearly complete compared
to the human HSA21q chromosome. Importantly, TcMAC21 mice exhibit penetrant AVSDs. We
propose to determine whether AVSDs in TcMAC21 result from failure of Hedgehog-signaling
dependent timing control of SHF cardiac progenitor differentiation timing. This Supplement
addresses INCLUDE Component 1: Targeted high risk - high reward basic science studies in
areas highly relevant to Down syndrome. We propose the transformative hypothesis that the
cause of cardiac defects in DS is failure of Hedgehog-signaling-dependent timing control of
progenitor differentiation, resulting in precocious differentiation, reduction of cardiac progenitor
numbers, and cardiac morphogenesis failure resulting in CHD.

## Key facts

- **NIH application ID:** 10747227
- **Project number:** 3R01HL147571-04S1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Ivan Paul Moskowitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $445,985
- **Award type:** 3
- **Project period:** 2022-12-26 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747227

## Citation

> US National Institutes of Health, RePORTER application 10747227, Evaluation of Hedgehog signaling-dependent heart development in a mouse model of Down Syndrome (3R01HL147571-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10747227. Licensed CC0.

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