# Trisomy 21 Model Atlas

> **NIH NIH R24** · UNIVERSITY OF COLORADO DENVER · 2023 · $736,765

## Abstract

PROJECT SUMMARY.
Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is the most prevalent chromosomal
abnormality and a leading cause of intellectual and developmental disability. T21 affects the development and/or
function of nearly every organ system, predisposing individuals with DS to many co-occurring conditions such
as Alzheimer’s disease, congenital heart defects, and autoimmune disorders, among others. Although it is
accepted that T21 causes genome-wide dysregulation of gene expression programs, little is known about how
T21 affects gene expression across different tissues and organs, and how these effects contribute to the etiology
of the co-occurring conditions of DS. Therefore, there is a clear need to understand the complex cause-effect
relationships between T21, altered gene expression, and organ development and pathophysiology.
Several mouse models of DS recapitulate key phenotypes of DS and have been used to study gene expression
dysregulation in DS. Additionally, induced pluripotent stem cell (iPSC) systems have been employed to study the
effects of T21 in human cell types. Therefore, in clear response to the Funding Opportunity Announcement PAR-
22-247, we propose here to generate a Trisomy 21 Model Atlas of tissue-specific murine and human
transcriptomes, matched to detailed metrics of organ development and architecture. The use of mouse
models will provide insights into tissue- and developmental stage-specific transcriptome changes and
pathophysiology, while human cell types differentiated from iPSCs will dissect cell-intrinsic features of T21 and
validate findings from the mouse models. Our Specific Aims are:
1. Generate an atlas of gene expression programs affected by trisomy 21 across model systems.
Supported by strong preliminary data, we propose here to complete an atlas of transcriptome changes in ten
organs across three developmental stages in mice and matched data from human cell types derived from iPSCs.
2. Define the impact of trisomy 21 on organ development and pathophysiology at the cellular level. To
investigate the link between dysregulated gene expression and tissue dysfunction, we will assess organ
development and pathophysiology through histopathological profiling, multiplexed immunofluorescence imaging,
single-cell RNA-sequencing, and characterization of human organoids derived from iPSCs.
3. Curate, organize, and share all data for open access through the INCLUDE Data Hub. We will ensure
that all data is made publicly available in the INCLUDE Data Hub by completing careful file curation and
organization, developing a metadata schema, and creating a code repository. This will ensure that the atlas
becomes a lasting resource that can be used beyond the scope of this grant.
Altogether, this resource will advance our understanding of the effects of T21 on organ development and
pathology, while enabling findings cross-validated in mouse models and human cell types.

## Key facts

- **NIH application ID:** 10769002
- **Project number:** 1R24OD035579-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joaquin M. Espinosa
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $736,765
- **Award type:** 1
- **Project period:** 2023-09-19 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769002

## Citation

> US National Institutes of Health, RePORTER application 10769002, Trisomy 21 Model Atlas (1R24OD035579-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10769002. Licensed CC0.

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