# Neonatal Modulation of Airway Contractility

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $655,864

## Abstract

ABSTRACT
Premature birth necessitates interventions such as supplemental O2 (hyperoxia; typically <60% O2) with/without
respiratory support primarily using non-invasive nasal CPAP. Studies from the previous cycle of this longstanding
R01 have shown neonatal O2 is associated with development of airway hyperreactivity (AHR) and remodeling
(cell proliferation, fibrosis): effects that contribute to a wheezing phenotype and predispose to asthma. While
CPAP is initially beneficial, long-term effects on highly compliant bronchial airways are less known. We previously
found static stretch of CPAP induces sustained AHR and airway thickening even after CPAP is stopped and
involves airway smooth muscle (ASM). What we do not fully understand are upstream mechanosensitive
transducers of stretch, and downstream pathways by which O2 and stretch interact to produce these effects,
Based on preliminary data, we hypothesize that mechanosensitive Piezo (PZ) channels in developing ASM
contribute to CPAP-induced AHR and remodeling. There are currently limited data on PZ channels in lung (which
does express them) and none in airways. Preliminary data show PZ1 and PZ2 are expressed in human fetal
ASM (fASM) and in neonatal mouse, and that PZs are functional in enhancing Ca2+ responses, proliferation and
ECM formation. 50% O2 and stretch each increase fASM PZ: effects also noted in newborn mice where 7 days
CPAP results in sustained AHR and remodeling at 3 wks, and inhibition of PZ blunts CPAP effects. Downstream
of PZ, we find that canonical Wnt/β-catenin signaling is important, and can be increased by stretch/CPAP. Our
overall hypothesis/model is that in developing airways, ASM PZ channels and downstream Wnt/β-catenin
pathways are linked in the context of O2 and/or stretch effects, leading to AHR and remodeling. Our 3 Specific
Aims to explore our model are: Aim 1: Determine the role of PZ channels in O2- and stretch-induced responses
of human fASM; Aim 2: Determine mechanisms that mediate PZ effects in O2 and stretch-induced human fASM
responses; Aim 3: In a neonatal mouse model of O2 and CPAP, determine role of PZ in AHR and remodeling. In
Aims 1 and 2, 18-22 wk human fASM cells are exposed to normoxia vs. moderate hyperoxia with/without static
stretch on a background of cyclic strain, mimicking clinical application of O2 +/- CPAP in spontaneously breathing
premies. In Aim 1, complementary imaging and biochemical techniques are used with PZ modulators to assess
roles of PZ in fASM [Ca2+]i (imaging), contractility (traction force microscopy), proliferation and fibrosis. In Aim 2,
complementary biochemical and molecular tools are used to examine mechanisms that are involved in PZ effects
on remodeling in particular with a focus on Wnt/β-catenin. In vitro results are integrated in Aim 3 using clinically-
relevant neonatal mouse models of moderate hyperoxia (50% O2) with/without intermittent CPAP applied for the
first 1 wk followed by 2 wks recovery in WT and inducible sm...

## Key facts

- **NIH application ID:** 10840958
- **Project number:** 5R01HL056470-22
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Y. S. Prakash
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $655,864
- **Award type:** 5
- **Project period:** 1996-05-03 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840958

## Citation

> US National Institutes of Health, RePORTER application 10840958, Neonatal Modulation of Airway Contractility (5R01HL056470-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10840958. Licensed CC0.

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