# Project-2: Modeling TE birth defects in animals

> **NIH NIH P01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $408,859

## Abstract

PROJECT 2 | PROJECT SUMMARY
Failure to separate the fetal foregut into distinct trachea and esophagus (TE) can result in a spectrum of life-
threatening tracheoesophageal defects (TEDs). The genetic etiology of TEDs is poorly understood, and risk
variants are known in only 12% of TED patients. Even in cases where the causative mutations are known such
as in developmental transcription factors (TFs), how they result in TEDs is unclear because up until recently the
mechanisms of TE morphogenesis were ill defined. We made significant progress in the previous award. Using
a combination of Xenopus and mouse embryology, we elucidated the conserved cellular events driving TE
morphogenesis and showed that disrupting any step can result in TED-like phenotypes. We used Xenopus
CRISPR screens to validate potential TED-causing variants from patient genome sequences. One major
discovery was that downstream of Hedgehog (HH) signaling and developmental TFs, endosome-mediated
membrane remodeling is required to separate the foregut into distinct TE tubes. Consistent with this, genome
sequencing of 185 TED patients from Project 1 revealed an enrichment of damaging variants in
membrane/vesicular trafficking genes including the endocytic adaptor ITSN1, which in preliminary data we
demonstrated is required for Xenopus TE morphogenesis. The goal of the CLEAR consortium Project 2 is to
define the developmental basis of TED with cellular resolution in animal models. We will: Determine the
mechanism by which endosome trafficking regulates TE morphogenesis (Aim1). Test the hypothesis that
developmental TFs control the cell-specific expression of effector proteins such as endosome trafficking
machinery or cargo (Aim2, in collaboration with Project 3). Assess the pathogenicity of patient variants in animals
testing the provocative hypothesis that endosomeopathies might be a major cause of TEDs (Aim3).

## Key facts

- **NIH application ID:** 10458161
- **Project number:** 2P01HD093363-06
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Aaron M Zorn
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $408,859
- **Award type:** 2
- **Project period:** 2017-08-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458161

## Citation

> US National Institutes of Health, RePORTER application 10458161, Project-2: Modeling TE birth defects in animals (2P01HD093363-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10458161. Licensed CC0.

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