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

描述（由申请方提供）：特发性肺纤维化（IPF）是一种致死性纤维化肺部疾病，无有效药物治疗。IPF的特征在于成纤维细胞/肌纤维母细胞病灶和过度的细胞外基质蛋白积聚，其中 成纤维细胞迁移到损伤区域和肌成纤维细胞分化起关键作用。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介导的信号传导受到FAK C-末端同源蛋白的限制，称为FAK相关非激酶（FRNK），我们的数据表明其作用是肺纤维化的核心。FRNK在人IPF纤维化病变中下调，其下调程度与IPF肺成纤维细胞中的迁移率密切相关。在肺纤维化的实验鼠模型中，FRNK方法的获得（和损失）证明FRNK通过多种机制对所得纤维化起内源性制动作用。基于这些研究，我们假设FRNK通过抑制肌成纤维细胞分化和成纤维细胞运动性作为肺纤维化的负调节剂，并且FRNK mRNA的病理学快速衰减是TGF-β 1在IPF肺成纤维细胞中增加的促纤维化作用的基础。为了检验这一假设，提出了三种具体的人工智能。在目的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传导途径，并检查体内FRNK获得的效果，特别是在肌成纤维细胞中，对纤维形成的影响。S100 A4表达增加与FRNK缺陷小鼠肺纤维化增加相关。在目的2中，我们将研究S100 A4在成纤维细胞迁移中的功能作用以及FRNK/FAK轴介导S100 A4表达细胞体内纤维化的机制。在目标3中，我们将确定IPF成纤维细胞中病理性FRNK下调的分子机制及其伴随的功能下游后果。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开发针对人类IPF的新型治疗方法。

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.