FGF9 REGULATION OF LUNG DEVELOPMENT AND PATHOGENESIS OF PLEUROPULMONARY BLASTOMA

描述（由申请人提供）：肺部疾病的起源通常在发育期间开始开始。解开调节发育的复杂机制对于理解发育性、遗传性和获得性肺病的发病机制至关重要。该提案的重点是成纤维细胞生长因子9（FGF 9）信号调节肺发育的机制。FGF 9在肺上皮和间皮中产生，并且在调节间质中具有主要作用，并且在调节肺上皮中具有次要的直接和间接作用。我们已经确定了一个前馈调节网络，涉及间充质FGF受体（FGFR）和Wnt/β-连环蛋白信号。在首次提交该提案以来发表的数据中，我们表明FGF和Wnt/β-连环蛋白途径在体内都起抑制头蛋白的作用。这一发现将间充质FGF-Wnt/β-catenin信号传导与调节上皮生长和分化的Bmp通路偶联。 了解发育机制的另一种方法是研究癌症的发病机制，癌症是一种通常与胚胎调节机制有关的疾病。肺间质中的FGF 9信号传导与人类肺部疾病之间的潜在联系涉及可遗传的儿科肺癌综合征，胸膜肺母细胞瘤（PPB）。PPB是有趣的，因为它来自胚胎未定型的肺间充质细胞。诱导过表达FGF 9的小鼠胚胎肺发生间质增生，其组织学类似于I型PPB，表明FGF 9可能参与PPB的发病机制。PPB的遗传起源被映射到microRNA（miRNA）加工基因DICER 1的功能缺失突变。初步和已发表的数据显示，发育中的肺上皮中的Dicer 1消融模拟PPB的早期囊性阶段。DICER 1突变的PPB肿瘤的免疫组织化学研究通常显示肺上皮中DICER 1表达降低。这些观察结果表明了一种解释PPB发病机制的模型，其中DICER 1处理的上皮miRNA减少导致上皮基因的过表达和刺激邻近间充质增殖的因子的产生，从而使间充质易于发生肿瘤转化。初步数据提供的证据表明，上皮来源的FGF 9介导了DICER 1功能丧失突变的一些致病后果。我们推测Fgf 9可能是一个主要的致病基因，直接由DICER 1介导的miRNA途径调节。 在本提案中，我们将：1）阐明间充质FGF和Wnt/<$-连环蛋白信号传导调节Noggin表达和BMP途径活性的机制; 2）在PPB小鼠模型中测试FGF 9是间充质增生的致病介质的假设; 3）比较由FGF 9和Wnt/<$-连环蛋白信号传导调节的肺间充质转录景观。- 连环蛋白信号传导和Fgf 9和Dicer 1小鼠模型与早期人PPB的PPB。

DESCRIPTION (provided by applicant: The origins of lung disease often begin during development. Unraveling the complex mechanisms that regulate development is essential for understanding the pathogenesis of developmental, genetic and acquired lung disease. This proposal is focused around the mechanisms by which Fibroblast Growth Factor 9 (FGF9) signaling regulates lung development. FGF9 is made in lung epithelium and mesothelium and has a major role in regulating mesenchyme and secondary direct and indirect roles in the regulation of lung epithelium. We have identified a feed-forward regulatory network that involves mesenchymal FGF receptor (FGFR) and Wnt/¿-catenin signaling. In data published since the first submission of this proposal, we showed that both FGF and Wnt/¿-catenin pathways function in vivo to suppress Noggin. This finding couples mesenchymal FGF-Wnt/¿-catenin signaling with Bmp pathways that regulate epithelial growth and differentiation. Another means to gain insight into developmental mechanisms is to study the pathogenesis of cancer, a disease which often co-opts embryonic regulatory mechanisms. A potential link between FGF9 signaling in lung mesenchyme and human lung disease involves the heritable pediatric lung cancer syndrome, pleuropulmonary blastoma (PPB). PPB is interesting because it arises from embryonic uncommitted lung mesenchymal cells. Mouse embryonic lung that was induced to overexpress FGF9 develops mesenchymal hyperplasia with histology that mimics that of type I PPB, suggesting that FGF9 might be involved in the pathogenesis of PPB. The genetic origins of PPB were mapped to loss-of-function mutations in the microRNA (miRNA) processing gene, DICER1. Preliminary and published data shows that Dicer1 ablation in developing lung epithelium mimics the early cystic stage of PPB. Immunohistochemical studies of PPB tumors with mutations in DICER1 often show decreased DICER1 expression in lung epithelium. These observations suggest a model to explain the pathogenesis of PPB in which decreased epithelial miRNAs processed by DICER1 results in overexpression of an epithelial gene(s) and production of a factor(s) that stimulates the proliferation of adjacent mesenchyme, predisposing the mesenchyme to neoplastic transformation. Preliminary data provides evidence that implicates epithelial-derived FGF9 in mediating some of the pathogenic consequences of loss-of-function mutations in DICER1. We hypothesize that Fgf9 may be a major pathogenic gene that is directly regulated by DICER1-mediated miRNA pathways. In this proposal, we will: 1) Elucidate the mechanism by which mesenchymal FGF and Wnt/ ¿-catenin signaling regulates Noggin expression and activity of the BMP pathway; 2) Test the hypothesis that FGF9 is a pathogenic mediator of mesenchymal hyperplasia in a mouse model for PPB; and 3) Compare the lung mesenchymal transcriptional landscape regulated by FGF9 and Wnt/¿-catenin signaling and by Fgf9 and Dicer1 mouse models for PPB with early stage human PPB.