The Impaired FRNK in IPF

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ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with no effective treatment. The biological processes that underlie the persistent fibrotic repair and their molecular drivers have yet to be fully elucidated. Focal adhesion kinase (FAK)-Related Non-Kinase (FRNK) acts as an endogenous brake on lung fibrosis. FRNK is downregulated in IPF lung tissues and IPF fibroblasts, and the extent of FRNK downregulation tightly correlates with rapidity of motility in IPF fibroblasts. FRNK inhibits myofibroblast differentiation. Importantly, FRNK deficiency exacerbates lung fibrosis in bleomycin-challenged mice. However, the underlying mechanism whereby FRNK downregulation drives fibrotic responses remains unknown. Talin plays a critical role in mechano-transduction and cell contraction through its links between integrins and cellular contraction machinery; therefore, this link functions as the ‘Mechano-Joint’ of Talin. Our preliminary data demonstrate that Talin plays an important role in myofibroblast survival through its ‘Mechano-Joint’. Talin is activated in response to transforming growth factor beta-1 (TGF-β1) and Talin downregulation induces myofibroblasts apoptosis. FRNK induces Talin cleavage and myofibroblast apoptosis. We hypothesize that FRNK induces myofibroblast apoptosis through disruption of ‘Mechano-Joint’ of Talin. Preliminary data show that FRNK downregulation promotes activation of Crk-associated substrate (Cas) and S100A4 expression, which contributes to an invasive fibroblast phenotype. Furthermore, preliminary data support that KH- type splicing regulatory protein (KSRP) promotes rapid FRNK mRNA decay, resulting in FRNK downregulation in IPF. We hypothesize that pathologic FRNK downregulation by KSRP orchestrates cooperative fibrotic signaling mediated by Talin, Cas, and S100A4, resulting in persistent fibrotic responses in IPF. Aim 1 will define the novel role of ‘Mechano-Joint’ of Talin in myofibroblast survival, and to examine the effects of gain of FRNK in myofibroblast on lung fibrosis in vivo. Aim 2 will determine the mechanism whereby impaired FRNK function increases Cas activation and S100A4 expression, and to examine the effect of gain of FRNK in S100A4- expressing cells, on fibrogenesis. Aim 3 will determine the mechanism whereby KSRP regulate FRNK function. These studies will support our long-term goal to utilize knowledge gained from these studies to develop novel therapeutic approaches for IPF in humans.