The Role of FAK-related-non-kinase (FRNK) in lung fibrosis

描述(申请人提供)：特发性肺纤维化(IPF)是一种致命的纤维性肺疾病，没有有效的药物治疗。IPF的特点是成纤维细胞/肌成纤维细胞灶和细胞外基质蛋白过度积聚，其中 成纤维细胞向损伤区的迁移和肌成纤维细胞的分化起着关键作用。粘着斑激酶(FAK)是一种非受体酪氨酸激酶，是细胞迁移和肌成纤维细胞分化所必需的。FAK介导的信号转导受到FAK的C末端同源蛋白的限制，该蛋白被称为FAK相关的非激酶(Frnk)，我们的数据表明其作用是肺纤维化的中心。FRNK在人肺间质纤维化病变中表达下调，其下调程度与肺成纤维细胞的迁移速度密切相关。在实验性的小鼠肺纤维化模型中，Frnk方法的获得(和丢失)表明，frnk通过多种机制对由此产生的纤维化起到内源性刹车的作用。在这些研究的基础上，我们假设FRANK通过抑制肌成纤维细胞的分化和成纤维细胞的运动而发挥肺纤维化的负调节作用，病理上FRANK mRNA的快速衰退是转化生长因子-β1在IPF肺成纤维细胞中增强促纤维化作用(S)的基础。为了检验这一假设，本文提出了三个具体的人工智能。在目标1中，我们将确定受损的frnk功能促进肌成纤维细胞分化的细胞内信号通路，并检测体内尤其是肌成纤维细胞中frnk的获得对纤维化形成的影响。在Frnk缺陷小鼠中，S100A4的表达增加与肺纤维化的增加有关。在目标2中，我们将研究S100A4在成纤维细胞迁移中的功能作用，以及FRANK/FAK轴在表达S100A4的细胞中介导体内纤维化形成的机制。在目标3中，我们将确定IPF成纤维细胞病理性frnk下调的分子机制，以及伴随而来的功能下游后果。这些研究将支持我们的长期目标，即利用从这些研究中获得的知识来开发针对人类IPF的新的治疗方法。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disorder with no effective medical treatment. IPF is characterized by fibroblastic/myofibroblastic foci and excessive extracellular matrix protein accumulation, in which fibroblast migration into the injured areas and myofibroblast differentiation play critical roles. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is required for cell migration and myofibroblast differentiation. FAK-mediated signaling is limited by an FAK's C-terminal homologous protein, known as FAK-related non-kinase (FRNK), whose action that our data suggest to be central to pulmonary fibrogenesis. FRNK is downregulated in human IPF fibrotic lesions and the extent of its downregulation tightly correlates with migration rate in IPF lung fibroblasts. In an experimental murine model of pulmonary fibrosis, gain (and loss) of FRNK approaches demonstrates that FRNK functions as an endogenous brake on the resultant fibrosis through multiple mechanisms. Based upon these studies, we hypothesize that FRNK acts as a negative regulator of lung fibrosis through inhibition of myofibroblast differentiation ad fibroblast motility, and that pathologically rapid decay of FRNK mRNA underlies the increased pro-fibrotic effect(s) of TGF-¿1 in IPF lung fibroblasts. To test the hypothesis, three specific ais are proposed. In Aim 1, we will determine the intracellular signaling pathway by which impaired FRNK function promotes myofibroblast differentiation, and examine the effect of gain of FRNK in vivo, specifically in myofibroblasts, on fibrogenesis. Increased S100A4 expression is associated with increased lung fibrosis in FRNK deficient mice. In Aim 2, we will examine the functional role of S100A4 in fibroblast migration and the mechanism whereby FRNK/FAK axis mediates in vivo fibrogenesis in S100A4-expressing cells. In Aim 3, we will determine the molecular mechanism of pathologic FRNK downregulation in IPF fibroblasts, and its attendant functional downstream consequences. These studies will support our long-term goal to utilize knowledge gained from these studies to develop novel therapeutic approaches targeted to IPF in humans.