# MESOTHELIAL MECHANOTRANSDUCTION AS A KEY REGULATOR OF EMBRYONIC LUNG GROWTH

> **NIH NIH F31** · UNIVERSITY OF DELAWARE · 2020 · $31,597

## Abstract

PROJECT SUMMARY/ABSTRACT
Congenital diaphragmatic hernia (CDH) affects 1 in 2500 live births with mortality rates in newborns ranging from
10-40%, depending on factors such as severity. CDH involves the herniation of the abdominal organs into the
chest cavity through a hole in the diaphragm and results in decreased lung growth, or pulmonary hypoplasia.
The mesothelium is a specialized epithelial tissue that lines the embryonic lung and has a major influence on
lung growth by secreting growth factors such as FGF9 and serving as a progenitor pool for various cells in the
growing lung. However, it is unclear what regulates these two phenomena. Previous data along with our
preliminary data has led to the hypothesis that these functions of the mesothelium are regulated by tissue stretch,
and this stretch is dysregulated during CDH. Herein, we propose the mechanism by which this stretch is sensed
by the mesothelium, along with the downstream signaling that leads to eventual FGF9 expression. Overall, the
mesothelium is understudied considering its major influence on lung growth, and we are the first to propose that
the mesothelium is mechanically stimulated during development.
In both Aims we will use our novel microfluidic chest cavity to examine the effects of mesothelial stretch on the
whole tissue level. With this device, we can control the fluid pressure internal and external of a mouse lung
explant to induce controlled stretch on the lung in a physiological 3D culture system. In our first Aim, we will
test our proposed pathway involving stretch mediated FGF9 signaling. We hypothesize that this stretch is sensed
via the mechanosensitive molecule YAP, which in other systems is stretch responsive. YAP then induces WT1
and RA signaling to cause FGF9 expression from the tissue. In addition to using our microfluidic chest cavity
studying whole tissue effects, we will also apply controlled stretch to isolated primary mesothelial cells using
microfluidic stretch membranes. We will test our hypothesis by examining the effect of stretch on the various
molecules in the YAP/WT1/RA/FGF9 pathway, and the effect on growth when this pathway is interrupted. In our
second Aim, we hypothesize that mesothelial stretch is sensed by YAP to induce epithelial-mesenchymal
transition(EMT). The mesothelium has been shown to undergo EMT as serve as a progenitor pool for various
lung tissue, and in other systems, YAP is a known inducer of EMT. We will determine the effect of stretch on
mesothelial EMT.

## Key facts

- **NIH application ID:** 10000129
- **Project number:** 5F31HL140781-03
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Rachel Gilbert
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,597
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000129

## Citation

> US National Institutes of Health, RePORTER application 10000129, MESOTHELIAL MECHANOTRANSDUCTION AS A KEY REGULATOR OF EMBRYONIC LUNG GROWTH (5F31HL140781-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000129. Licensed CC0.

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