Myofibroblast differentiation and fibrosis are mediated by TRPV4 mechanosensing

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disorder with no effective medical treatment. The biological processes that underlie fibrotic lung repair and their molecular drivers have yet to be fully elucidated. Myofibroblasts are critica to the in vivo fibrogenic tissue repair process. Although both a mechanical signal (internally-generated cell tension, matrix stiffness), and a TGF-?-initiated signal are essential for optimal mature myofibroblast differentiation, the actual molecular pathway by which the mechanical signal is transduced/maintained, or its downstream consequences on in vivo fibrosis, are not known. We have made the novel observation that an ion channel in the transient receptor potential vanilloid family (TRPV4) serves as a mechanosensor/transducer to promote myofibroblast differentiation. This mechanosensitive, calcium permeable channel is rapidly activated upon local plasma membrane stretching. The hypothesis that TRPV4 mediates myofibroblast differentiation and pulmonary fibrogenesis by potentiating the TGF-? signal in a matrix stiffness, and PI3K-dependent manner, will be tested in three specific aims. The work in Aim 1 will determine the mechanism whereby the TRPV4 channel function is increased in response to TGF-?. The work in Aim 2 will determine how the PI3K intracellular signaling pathway affects TRPV4 function to mediate myofibroblast differentiation. Through this work, the underlying mechanism for the observed upregulation of TRPV4 activity in lung fibroblasts from idiopathic pulmonary fibrosis patients will be defined. The work in Aim 3 will determine the role of TRPV4 in pulmonary fibrogenesis in vivo, in two distinct murine models of pulmonary fibrosis. When completed, this work will provide conclusive evidence for the mechanism of TRPV4 channel's effect on myofibroblast differentiation, its intracellular signaling pathway, and the rol of TRPV4 in experimental pulmonary fibrosis.