# Type I IFN signaling during lung development in Down Syndrome-Multiome sequencing of human fetal and pediatric trisomy 21 lungs

> **NIH NIH R01** · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · 2022 · $352,785

## Abstract

Summary/Abstract
 Trisomy 21 (T21) is the most common human chromosomal anomaly, affecting 1 in 700 live births,
resulting in Down Syndrome (DS). Although DS can affect many organ systems, lung and heart disease are the
leading causes of morbidity and mortality. Several congenital lung anomalies are reported in individuals with DS
including airway branching defects, with a 25% decrease in the number of branches and reduced upper airway
muscle tone with dysphagia and/or bronchomalacia. These complications remain constant into adulthood, as
opposed to becoming exacerbated, and are hence likely due to developmental insufficiency.
 While abnormal pulmonary structure and function in pediatric and adult individuals with DS has been
described, there is limited data defining the ontogeny of these abnormalities. We postulated that developmental
differences could initiate prenatally in T21 lungs and have now demonstrated pulmonary anomalies arise in
approximately 70% of T21 cases starting as early as 16 weeks gestation, as determined from experiments
proposed in the parent grant. Our single cell RNAseq data and immunofluorescent stainings have demonstrated
upregulation of the surfactant metabolism pathway and increased cell number of differentiated proximal airway
markers (SCGB1A1 and FOXJ1) respectively. Altogether these findings strongly support one of the hypotheses
proposed in the parent grant, where we postulate precocious development/differentiation in the T21 lungs as
compared to their age and sex matched controls. These observations are fitting being that DS is generally
described as a progeroid syndrome. It has been demonstrated that this accelerated aging may be associated to
genome wide perturbation due to dysregulated epigenetic regulation; however, no studies have investigated the
epigenetic landscape of the developing T21 lung. Thus, we hypothesize cellular and molecular abnormalities in
T21 lungs initiate in utero, resulting in precocious development associated with altered epigenetic regulation.
Recent advances in single cell epigenetic profiling methodology allow us to simultaneously test this hypothesis
in the same tissues we are collecting and analyzing for the parent project. We will use multiome sequencing
(single nuclear RNAseq/ATACseq) to determine the cellular and molecular abnormalities initiated during the late
pseudoglandular/early canalicular stages of fetal development in T21 lungs. Being that epigenetic modifications
are preserved in daughter cells, we will also determine alterations in gene regulatory networks at the single cell
level between prenatal and postnatal T21 lungs vs non-T21 lungs, to further define the ontogeny of pulmonary
anomalies observed in DS.
 These studies have the promise to improve our understanding of the key molecular and cellular
differences, and the mechanisms controlling defects in T21 developing lungs. The innovative aspects of this
work are likely to have great overall impact in stimulating additi...

## Key facts

- **NIH application ID:** 10670654
- **Project number:** 3R01HL155104-01A1S1
- **Recipient organization:** LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
- **Principal Investigator:** Soula Athanasia Danopoulos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $352,785
- **Award type:** 3
- **Project period:** 2021-09-17 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670654

## Citation

> US National Institutes of Health, RePORTER application 10670654, Type I IFN signaling during lung development in Down Syndrome-Multiome sequencing of human fetal and pediatric trisomy 21 lungs (3R01HL155104-01A1S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10670654. Licensed CC0.

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