# Trisomy 21 and its impact on hedgehog-dependent gene regulation and  differentiation timing

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $77,867

## Abstract

PROJECT SUMMARY
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. Specific types of CHD developed by DS patients affect posterior
cardiac structures more severely and frequently than anterior structures. A mechanistic
understanding of DS-specific organogenesis defects is lacking in most cases, although a rich
descriptive literature sets the stage for concerted mechanistic studies. Specifically, how Trisomy
21 (T21) causes heart morphogenesis defects, causing posterior vs anterior CHD, is poorly
understood. The molecular networks identified by the proposed work, implicated in DS organ-
specific cardiac progenitors, will serve as a template for understanding the molecular ontogeny of
heart defects. We have defined Hedgehog (Hh) signaling as an explicit development timer during
mammalian development, required for maintaining organ-specific progenitor cells and dictating
their differentiation in time and space, independent from developmental patterning or proliferation.
Additionally, during cardiac development retinoic acid is crucial for establishing anteroposterior
polarity and specifically promoting the posterior limits of the SHF. These signaling pathways
together control the balance between organ-specific progenitors and their differentiated
counterparts that is fundamental to complex organogenesis of the heart. The Moskowitz lab found
that when Hh signaling is abrogated in cardiac progenitors, they underwent precocious
differentiation, resulting in morphogenesis failure. Aligned with the parent award, we propose the
transformative hypothesis that a unifying cause of birth defects in DS is failure of heterochronic
timing control of organ-specific progenitor differentiation, resulting in precocious differentiation, a
reduction of organ-specific progenitors, morphogenesis failure and birth defects in multiple
organs.

## Key facts

- **NIH application ID:** 11090045
- **Project number:** 3R01HD111938-01S1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Ivan Paul Moskowitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,867
- **Award type:** 3
- **Project period:** 2024-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11090045

## Citation

> US National Institutes of Health, RePORTER application 11090045, Trisomy 21 and its impact on hedgehog-dependent gene regulation and  differentiation timing (3R01HD111938-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11090045. Licensed CC0.

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