# Determining the neurodevelopmental cell type specific regulatory networks impacted in Down syndrome

> **NIH NIH R03** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $98,300

## Abstract

ABSTRACT
Abstract of the funded parent grant: Down syndrome is the most prevalent genetic condition in humans and a
major cause of intellectual disability. Although the severity and extent of phenotypes present in Down
syndrome partially result from an extra copy of chromosome 21, details regarding the biological mechanisms
and the emergence of atypical development are not understood. To address this significant gap in knowledge,
we previously created a ‘Developmental Cell Atlas of Down Syndrome’ by using single-cell RNA-sequencing to
profile the transcriptomes of over 700,000 cells derived from multiple tissues. This proposal represents our
ongoing efforts to characterize the molecular and cellular identity of cellular phenotypes present in the
developing brain in Down syndrome. In Aim 1, we will map the Down syndrome cells onto a reference
framework of the developing human brain by pooling existing single-cell RNA-sequencing data. In Aim 2, we
will use our established human brain functional genomics pipeline to infer cell-type-specific gene regulatory
networks altered in Down syndrome. Leveraging existing data, this study will provide critical information about
the emergence and regulation of early brain development in Down syndrome that can be used to elucidate the
molecular mechanisms underlying early neuropathology and to benchmark model systems for disease relevant
neuronal phenotypes.
Abstract of the requested supplement: This application is being submitted for PA-20-272 in accordance with
NOT-OD-21-076. The goal of this research supplement is to experimentally validate the findings from our cell-
type specific gene regulatory network analysis using high resolution chromatin mapping. We propose to use
single cell chromatin mapping in control and trisomy 21 developing brain tissue. We will integrate these new
data with our existing single-nucleus gene expression data to confirm the gene regulatory networks predicted
via our human brain functional genomics pipeline. Successful completion of the supplementary aims will define
gene regulatory networks that are perturbed in Down syndrome brain development and form the basis of future
studies aimed at elucidating the cellular and molecular consequences that precede clinical phenotypes.

## Key facts

- **NIH application ID:** 10595260
- **Project number:** 3R03NS123969-01S1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Kimberly Anne Aldinger
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $98,300
- **Award type:** 3
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10595260

## Citation

> US National Institutes of Health, RePORTER application 10595260, Determining the neurodevelopmental cell type specific regulatory networks impacted in Down syndrome (3R03NS123969-01S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10595260. Licensed CC0.

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