# Mechanisms controlling early human lung development

> **NIH NIH R01** · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · 2020 · $432,443

## Abstract

Abstract:
Down syndrome (DS) is the most common human chromosomal anomaly and affects 1 in 800 newborns in the
United States. Although Down syndrome can affect many organ systems, lung and heart disease are the
leading causes of death at all ages in DS. Several congenital lung anomalies are reported in DS patients
including airway branching defects, with a 25% decrease in number of branch generations, pulmonary
hypoplasia, cystic lesions and vascular defects leading to pulmonary hypertension. In addition, DS patients can
present with reduced upper airway muscle tone with dysphagia and/or bronchomalacia. We have developed a
human ex vivo lung branching morphogenesis model that allows for branching quantification in real time, and
in which we can interrogate the contributions of smooth muscle. Our preliminary data suggests that defects in
SMC peristalsis appear to impair branching in human DS lung explants. We have also recently demonstrated
the ability to transcriptionally profile mesenchymal smooth muscle cell diversity in normal human fetal lung
tissues. Our preliminary data identify molecular markers unique to defined populations including vascular and
airway smooth muscle cells. Therefore, we hypothesize that abnormal lung development in DS is caused by
cell autonomous deficiencies in smooth muscle cell function, phenotype and heterogeneity. In aim 1, we will
test the hypothesis that airway branching-associated function and phenotype of lung SMCs is impaired in DS
using our ex vivo fetal human lung culture system to further examine branching and peristalsis in DS fetal lung
tissues. We will also test whether calcium-mediated changes in SMC contraction and peristalsis are normal in
DS lung SMCs. In aim 2, we will determine whether airway smooth muscle cell diversity is abnormal in DS fetal
lung using single cell transcriptomics to assess the diversity of SMC phenotypes in normal and DS fetal lung.
We will also define the specificity of any alterations by simultaneously comparing normal and DS lung vascular
smooth muscle cell phenotypic heterogeneity. Our proposed studies will be the first to test novel hypotheses
about primary deficiencies in early DS lung SMC phenotypes and function using cutting-edge methods that will
provide insight at the physiological, morphogenic, cellular and molecular levels. Improved strategies to prevent,
ameliorate or reverse lung disease in DS will be contingent upon a detailed understanding of the pathogenesis
of these diseases. The studies proposed here are designed to provide fundamental knowledge about the
abnormal pathophysiology contributing to developmental abnormalities in DS lung, and may identify
therapeutic targets for intervention.

## Key facts

- **NIH application ID:** 10310255
- **Project number:** 7R01HL141856-04
- **Recipient organization:** LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
- **Principal Investigator:** Denise Al Alam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,443
- **Award type:** 7
- **Project period:** 2018-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310255

## Citation

> US National Institutes of Health, RePORTER application 10310255, Mechanisms controlling early human lung development (7R01HL141856-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10310255. Licensed CC0.

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