# Mechanical Control of Cell Proliferation and Branching Morphogenesis in the Embryonic Lung

> **NIH NIH R01** · UNIVERSITY OF TEXAS DALLAS · 2022 · $380,247

## Abstract

PROJECT SUMMARY/ABSTRACT
In the embryonic lung, the bronchial tree is sculpted by a process known as branching morphogenesis. Defects
in branching can cause a variety of congenital malformations, such as pulmonary hypoplasia, which
compromises respiratory function due to decreased lung growth. Several of these defects are caused by
changes in the mechanical environment of the fetal lung, but it remains unclear how physical cues in the tissue
microenvironment direct the formation of the bronchial tree. Dynamic, quantitative studies of branching
morphogenesis are needed to unravel the regulatory role of mechanical forces during lung development. We
hypothesize that airway branching is driven by a mechanical feedback mechanism, in which patterns
of mechanical stress regulate the patterns of epithelial proliferation that sculpt the developing airways.
To test this hypothesis, we will use novel experimental platforms that allow us to control and quantify the
mechanical stresses within the embryonic airway epithelium. We recently developed a novel three-dimensional
(3D) traction force microscopy (TFM) assay for cultured embryonic organ explants, as well as a microfluidic
system to apply controlled fluid pressures to intact embryonic mouse lungs. These techniques will be combined
with dynamic studies of cell proliferation and fibroblast growth factor (FGF) signaling, as well as a novel
computational model of airway branching morphogenesis, to determine how physical cues regulate the growth
and remodeling of the embryonic lung. In Aim 1, we will determine how mechanical stress regulates patterns of
proliferation in isolated airway epithelial explants. Then, in Aim 2, we will use whole lung explant culture to
uncover how mechanical forces interact with FGFs to direct both normal and hypoplastic branching
phenotypes. Achieving these aims will help identify new therapeutic targets for diseases, such as congenital
diaphragmatic hernia, where airway branching morphogenesis and lung growth are severely impaired. These
results will also help guide pulmonary tissue engineers in their efforts to recapitulate aspects of embryonic
development in the laboratory to construct engineered lung tissue.

## Key facts

- **NIH application ID:** 10323018
- **Project number:** 5R01HL145147-04
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** Victor D. Varner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $380,247
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10323018

## Citation

> US National Institutes of Health, RePORTER application 10323018, Mechanical Control of Cell Proliferation and Branching Morphogenesis in the Embryonic Lung (5R01HL145147-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10323018. Licensed CC0.

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