# Temporal regulation of BMP signaling in patterning the tracheal cartilage and pharmacological approaches to prevent tracheomalacia

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $390,000

## Abstract

ABSTRACT
Tracheomalacia is the most common structural abnormality in the lower airway. The estimated incidence in
children ranges from 1 in 1,500 to 1 in 2,500. Tracheomalacia is very often associated with congenital
syndromic disorders and congenital tracheomalacia associated with impaired cartilage integrity often
represents the ones with severe symptoms, less regression percentage and higher mortality rate. Currently,
surgical intervention is the only option, which requires disproportionately high allocation of health care
resources. The lack of knowledge on the tracheal cartilage development and the pathophysiological
mechanisms lead to impaired tracheal cartilage integrity prevent searching for alternative interventions for
congenital tracheomalacia. BMP signaling has been demonstrated as a critical growth factor necessary for
chondrogenesis and cartilage development, however, how BMP signaling is regulated during tracheal cartilage
development has not been investigated. EvC syndrome (OMIM 225500) is an autosomal recessive
chondrodysplasia. Neonatal death subsequent to airway collapse has been documented in patients with EvC
syndrome. Our preliminary studies using Evc2 mutant mice uncover the potential novel mechanisms on the
regulated BMP signaling both in foregut mesenchyme and in tracheal mesenchyme. We have demonstrated
that well-orchestrated BMP signaling in foregut and tracheal mesenchyme is necessary for tracheal cartilage
developing into correct shape. Our preliminary studies lead us hypothesize that: Hedgehog-BMP axis at
foregut mesenchyme determines the BMP signaling levels in tracheal mesenchyme and the subsequent
chondrogenesis; after trachea and esophagus separation, extracellularly stored BMP ligands play a critical role
in inducing BMP signaling in tracheal mesenchyme for subsequent chondrogenesis; and that administration of
FK506 has the potential to correct the congenital defective tracheal cartilage in Evc2 mutant mice. This
hypothesis will be investigated by the following three aims: 1) To demonstrate that the Hedgehog-BMP axis
within the foregut mesenchyme is critical for tracheal cartilage development; 2) To evaluate roles of
mesenchymally synthesized and extracellularly stored BMP ligands in inducing chondrogenic differentiation in
tracheal mesenchyme; 3) To demonstrate that pharmacological elevation of BMP signaling will rescue the
defects in tracheal cartilage development. The outcome of the proposed work will uncover the molecular
networks govern the tracheal cartilage development, which will directly set up the knowledge base for the
practical therapeutic solutions.

## Key facts

- **NIH application ID:** 10417330
- **Project number:** 1R01HL162939-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Yuji MISHINA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,000
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417330

## Citation

> US National Institutes of Health, RePORTER application 10417330, Temporal regulation of BMP signaling in patterning the tracheal cartilage and pharmacological approaches to prevent tracheomalacia (1R01HL162939-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10417330. Licensed CC0.

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