# Identifying Gli-Regulated Targets during Tracheal Development and Disease

> **NIH NIH F30** · UNIVERSITY OF CINCINNATI · 2020 · $45,659

## Abstract

Project Summary/Abstract
This goal of this project is to identify the mechanisms by which Hedgehog/Gli signaling regulates tracheal
development and how disruptions in this process can lead to perinatal tracheal defects. Errors in tracheal
development may range from tracheal atresia and tracheoesophageal (TE) clefts, where the fetal foregut tube
fails to separate properly, to tracheomalacia due to impaired tracheal chondrogenesis. The etiology of tracheal
defects is poorly understood and new diagnoses and therapies are needed to address these relatively common
yet potentially lethal defects. Human patient exome sequencing as well as murine mutant models have begun
to identify a few developmental pathways that regulate tracheal development, including the Hedgehog/Gli
pathway. For example, in murine models a total loss of Gli2 and Gli3 results in a complete failure of tracheal
development, while some compound heterozygous Gli2;Gli3 mutants exhibit a TE cleft with tracheomalacia. In
addition, our preliminary data suggests that transgenic expression of a Gli3 mutant that mimics the genetic
lesion found in human Pallister-Hall syndrome patients also leads to impaired TE separation and virtually
absent tracheal cartilage.
The specific aims of this project are to identify Gli target genes in the developing trachea, to determine how Gli
regulates TE separation and tracheal cartilage differentiation, and to model the mechanism of human tracheal
defects. Preliminary RNA-seq studies of control and mutant foreguts have begun to define Gli targets during
TE development. I will test the hypothesis that these candidate Gli target genes are misexpressed and/or
mislocalized during TE development in Gli mutants. Our preliminary further data suggest that Wnt and
BMP pathways act downstream of HH/Gli, and we will use a combination of mouse genetics and fetal foregut
cultures to test the hypothesis that defective Wnt and BMP signaling is responsible for the defects in tracheal
chondrogenesis. The results of these experiments will inform the basis of tracheal defects in human patients
and as well as guide differentiation of tracheal iPSCs towards new therapeutic possibilities. This project will
also provide valuable training in current clinical diagnosis and treatment strategies for these patients.
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## Key facts

- **NIH application ID:** 10195097
- **Project number:** 7F30HL142201-04
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Talia S Nasr
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,659
- **Award type:** 7
- **Project period:** 2018-04-20 → 2022-04-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10195097

## Citation

> US National Institutes of Health, RePORTER application 10195097, Identifying Gli-Regulated Targets during Tracheal Development and Disease (7F30HL142201-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10195097. Licensed CC0.

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