# TRPV4-PI3K Axis Mediates Pulmonary and Cardiac Fibrosis

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $563,500

## Abstract

ABSTRACT
Pathologic fibrosis of the heart or lung results in fatal organ failure with no current cure, short of
transplantation. In order to successfully ameliorate cardiac and pulmonary fibrotic disorders, a better
understanding of the pathogenesis of organ fibrosis is vital. Fibrogenesis among organs exhibit both common
and unique features. Among these, myofibroblasts are key common, fibrosis-effector cells. It has long been
known that the response to changes in the mechanical properties of the surrounding tissue/matrix, along with
active TGF-β, are critical drivers of myofibroblast differentiation. Although integrins and other receptors
participate in cell-matrix interactions, the specific mechanosensor driving myofibroblast has remained elusive.
We have recently identified TRPV4 as the critical mechanosensor for driving both myofibroblast differentiation
and fibrosis in the lung. TRPV4 is a stretch-activatable, plasma membrane cation channel in the transient
receptor potential, vanilloid family (TRPV4). Moreover, TRPV4 drives myofibroblast differentiation and fibrosis
at levels of matrix stiffness that are directly biologically and clinically relevant to cardiac and pulmonary
disease. We have confirmed recent observations demonstrating TRPV4's importance to cardiac myofibroblast
differentiation, and our novel preliminary data further suggests that both the heart and lung pro-fibrotic signals
depends on TRPV4's signal pathway interactions with the γ-isoform of PI3K. Based on this data, we have
formulated the novel hypothesis that the TRPV4-PI3Kγ signaling axis mediates mechanotransduction
that drives myofibroblast differentiation and fibrosis in both the heart and lung. Intriguingly, the details of
how TRPV4-PI3Kγ interact to drive fibrosis appear to quite different and organ-specific. Two coordinated
specific aims will determine the mechanism whereby TRPV4-PI3Kγ mechanosignal transduction pathways
mediate myofibroblast differentiation and fibrosis in the heart and lungs, respectively. These aims will use gain
and loss function experimental designs with both genetic and pharmacologic approaches to determine the key
TRPV4-PI3Kγ pathway interactions that drive myofibroblast differentiation and fibrosis. TRPV4-PI3Kγ axis will
be interrogated using hierarchical experimental systems at the cellular level, at the level of established
experimental murine models, and at the level of human disease. When complete, we will have a detailed and
comprehensive understanding of the precise mechanism by which the TRPV4-PI3Kγ axis mediates cardiac
and pulmonary fibrosis. As several small molecule, selective inhibitors of both PI3Kγ and TRPV4 are in various
phases of development, the knowledge gained from this “proof of concept” study could rapidly translate into
novel therapeutic approaches for both cardiac and pulmonary fibrotic disorders.

## Key facts

- **NIH application ID:** 9956628
- **Project number:** 5R01HL133721-04
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Mitchell Alan Olman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $563,500
- **Award type:** 5
- **Project period:** 2017-08-09 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9956628

## Citation

> US National Institutes of Health, RePORTER application 9956628, TRPV4-PI3K Axis Mediates Pulmonary and Cardiac Fibrosis (5R01HL133721-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9956628. Licensed CC0.

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