# Lung Development and Diseases

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2022 · $513,404

## Abstract

Project Summary/Abstract
Abnormal lung development results in a variety of congenital respiratory diseases contributing to neonatal
morbidity and mortality. Although BMP signaling is known to be important in lung organogenesis,
understanding of BMP in lung development and pulmonary diseases is incomplete. In particular, BMP signaling
in developing lung mesenchyme has not been studied due to embryonic lethality in mice with global abrogation
of BMP pathway and the lack of genetic tools to target lung mesenchyme. Using our new Tbx4 lung enhancer-
driven loxP/Cre system, lung mesenchymal BMP receptor IA (Bmpr1a) has been specifically deleted. The
knockout mice have abnormal airway branching and cystic malformation, which resembles the pathology of
congenital pulmonary airway malformation seen in human patients. Deficiencies of airway smooth muscle cells
and subepithelial elastin fibers, abnormal mesenchymal expression of Bmp ligands, as well as airway epithelial
perturbation of Sox2-Sox9 progenitor axis are found in the cystic lungs of the Bmpr1a knockout mice. In
addition, we found that Bmpr1a-mediated Smad-independent signaling regulated airway smooth muscle cell
growth and elastin expression in vitro and in vivo. Thus, we hypothesize that mesenchymal Bmpr1a-mediated
Smad-independent signaling is essential for airway smooth muscle cell differentiation and subepithelial elastin
production as well as suppression of Bmp ligand expression. Combined disruption of these processes results
in abnormal airway development and subsequent prenatal airway cystic malformation. Two specific aims are
proposed: (1) To determine the pathogenic mechanisms by which defective mesenchymal BMP signaling
causes congenital lung malformation through disruption of the airway smooth muscle and subepithelial elastin
layer. Mesenchymal Bmpr1a will be deleted in embryonic mouse lung. The lung mesenchymal abnormality and
its contribution to airway cystic malformation will be determined from histologic structure to cellular and
molecular changes. The underlying molecular mechanisms from BMP intracellular signaling (Smad-
independent pathway) to decreased Myocd expression/SMC differentiation and deficiency of subepithelial
elastin production will then be studied using both in vivo and in vitro approaches. (2) To determine the
mechanisms by which mesenchymal deficiency of Bmpr1a indirectly results in abnormal airway epithelial
growth and overall airway abnormality. The airway epithelial abnormality resulting from mesenchymal Bmpr1a
deletion will be analyzed. The mechanisms by which mesenchymal deficiency of Bmpr1a signaling results in
abnormal mesenchymal-epithelial crosstalk through mesenchymal misexpression of Bmp ligands will be
studied. The role of the resultant airway epithelial Sox2+ progenitor deficiency and Sox9+ progenitor expansion
in contributing to the lung abnormality will also be investigated.

## Key facts

- **NIH application ID:** 10366936
- **Project number:** 1R01HL151699-01A1
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** WEI SHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $513,404
- **Award type:** 1
- **Project period:** 2022-02-15 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366936

## Citation

> US National Institutes of Health, RePORTER application 10366936, Lung Development and Diseases (1R01HL151699-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366936. Licensed CC0.

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