The Impaired FRNK in IPF

摘要 特发性肺纤维化(IPF)是一种没有有效治疗方法的纤维性肺部疾病。这个 持续性纤维化修复的生物过程及其分子驱动因素 尚未完全阐明。粘着斑激酶(FAK)相关的非激酶(Frnk)作为一种 肺纤维化的内源性刹车。FRANK在IPF肺组织和IPF中表达下调 FRANK下调的程度与血管内皮细胞的运动速度密切相关。 IPF成纤维细胞。FRNK抑制肌成纤维细胞分化。重要的是，Frnk缺乏症 加剧博莱霉素攻击小鼠的肺纤维化。然而，潜在的机制 目前尚不清楚frnk下调是如何驱动纤维化反应的。塔林扮演着关键的角色 整合素与细胞间的联系在机械转导和细胞收缩中的作用 收缩机械；因此，这个连杆起着塔林的‘机械关节’的作用。我们的 初步数据显示Talin在肌成纤维细胞存活中起重要作用 这是“机械式关节”。TALIN被转化生长因子β-1(转化生长因子-β1)激活 Talin基因下调可诱导肌成纤维细胞凋亡。Frnk诱导Talin卵裂和 肌成纤维细胞凋亡。我们推测frnk通过以下途径诱导肌成纤维细胞凋亡 破坏了塔林的“机械关节”。初步数据显示，法国下调了监管 促进Crk相关底物(Cas)和S100A4的表达，从而 有助于侵袭性成纤维细胞表型。此外，初步数据支持KH- 类型剪接调节蛋白(KSRP)促进frnk mRNA快速降解，导致frnk 在IPF中下调监管。我们假设KSRP对病理性Frnk的下调 协调Talin、Cas和S100A4介导的协作性纤维化信号，导致 IPF中的持续性纤维化反应。目标1将定义塔林在《机械关节》中的新角色 肌成纤维细胞的存活，并检测肌成纤维细胞中FRNK的获得对肺的影响 体内纤维化。目标2将确定受损的frnk功能增加的机制。 CaS激活和S100A4的表达，并检测增强型FRANK对S100A4- 在纤维化形成过程中，表达细胞。目标3将确定KSRP调节机制 FRNK函数。这些研究将支持我们的长期目标，即利用从 这些研究旨在为人类的IPF开发新的治疗方法。

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.