# Profibrotic Mechanisms of the TRPV4-PI3K-gamma Protein Complex

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $402,500

## Abstract

ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a fatal disorder with urgent need for a medical cure. In order to
successfully ameliorate pulmonary fibrosis, a better understanding of fibrotic pathogenesis is vital.
Myofibroblasts are key 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 differentiation has remained elusive. We have 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 pulmonary disease. We have demonstrated TRPV4’s importance
to myofibroblast differentiation and experimental pulmonary fibrosis and human IPF. Our novel published and
preliminary data further suggests that TRPV4’s pro-fibrotic actions depend on its biochemical association with
cytosolic PI3Kγ via PI3kγ’s unique aminoterminal, non-catalytic domain, followed by the translocation of the
protein complex to the plasma membrane. Based on this data, we have formulated the novel hypothesis that
the TGFβ drives myofibroblast differentiation and pulmonary fibrosis by inducing the TRPV4-PI3Kγ
protein complex to translocate to the plasma membrane. Three coordinated specific aims with gain and
loss function experimental designs will determine the key TRPV4-PI3Kγ pathway interactions that drive
myofibroblast differentiation and fibrosis. They will utilize gain and loss of function design in in silico, in vitro
and in vivo systems at the structural level, cellular level, and at the levels of established experimental murine
models, and in human disease. AIM 1 will precisely define the amino acid(s) interacting sites between TRPV4
and PI3Kγ, AIM 2 will determine the mechanism whereby TGFβ induces the translocation of TRPV4-PI3Kγ
complexes to the PM where they act to drive myofibroblast differentiation and AIM 3 will test the concept that
the aminoterminal domain of PI3Kγ is necessary and sufficient to drive pulmonary fibrosis in vivo. All key
findings will be validated in normal and IPF patient-derived cells and tissue. When complete, we will have a
detailed and comprehensive understanding of the precise mechanism by which the TRPV4-PI3Kγ axis
mediates 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 pulmonary fibrotic disorders.

## Key facts

- **NIH application ID:** 10277829
- **Project number:** 1R01HL158746-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Mitchell Alan Olman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,500
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10277829

## Citation

> US National Institutes of Health, RePORTER application 10277829, Profibrotic Mechanisms of the TRPV4-PI3K-gamma Protein Complex (1R01HL158746-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10277829. Licensed CC0.

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