FGF9 REGULATION OF LUNG DEVELOPMENT AND PATHOGENESIS OF PLEUROPULMONARY BLASTOMA

FGF9对肺发育和胸膜肺母细胞瘤发病机制的调节

• 批准号: 8535194
• 负责人: David M Ornitz
• 金额: $ 48.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535194
• 关键词: Ablation; Address; Alleles; Cause of Death; Cells; Childhood; Complex; Coupled; Couples; Coupling; DICER1 gene; Data; Development; Diagnosis; Diagnostic; Differentiation and Growth; Disease; Disease Progression; Embryo; Embryonic Development; Epithelial; Epithelium; Etiology; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Genes; Genetic; Histology; Human; Hyperplasia; Knowledge; Life; Link; Lung; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Mediator of activation protein; Mesenchymal; Mesenchyme; Mesothelium; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Mutation; Natural regeneration; Neoplastic Cell Transformation; Pathogenesis; Pathway interactions; Phenotype; Pleuropulmonary Blastoma; Process; Processed Genes; Production; Publishing; Receptor Signaling; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Syndrome; Testing; Therapeutic; United States; design; developmental genetics; disability; feeding; fibroblast growth factor 9; in vivo; insight; interest; loss of function; loss of function mutation; lung development; lung repair; mRNA Expression; mouse model; next generation; overexpression; tumor

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.

描述（由申请人提供：肺部疾病的起源通常始于发育过程。揭示调节发育的复杂机制对于理解发育性、遗传性和获得性肺部疾病的发病机制至关重要。该提案重点关注成纤维细胞生长因子的作用机制FGF9 (FGF9) 信号传导调节肺发育 FGF9 在肺上皮和间皮中产生，在调节间质中起主要作用，并在肺调节中发挥直接和间接的次要作用。我们已经确定了一个涉及间充质 FGF 受体 (FGFR) 和 Wnt/¿ -连环蛋白信号传导的前馈调节网络。自首次提交该提案以来发布的数据中，我们表明 FGF 和 Wnt/¿ -连环蛋白通路。这一发现将间充质 FGF-Wnt/¿ -连环蛋白信号与调节上皮生长和分化的 Bmp 通路结合起来。癌症的发病机制是一种经常与胚胎调节机制相结合的疾病，肺间质中的 FGF9 信号传导与人类肺部疾病之间的潜在联系涉及遗传性小儿肺癌综合征，即胸膜肺母细胞瘤 (PPB)，这一点很有趣，因为它起源于 PPB。诱导过度表达 FGF9 的胚胎未定型肺间充质细胞发生间充质增生，其组织学类似于 I 型。 PPB，表明 FGF9 可能参与 PPB 的发病机制 PPB 的遗传起源被映射为 microRNA (miRNA) 处理基因 DICER1 的功能丧失突变。 DICER1 突变的 PPB 肿瘤的免疫组织化学研究通常显示肺上皮中 DICER1 表达降低。观察结果提出了一个解释 PPB 发病机制的模型，其中 DICER1 处理的上皮 miRNA 减少导致上皮基因过度表达并产生刺激邻近间质增殖的因子，使间质易于发生肿瘤转化初步数据提供的证据表明上皮源性 FGF9 介导了 DICER1 功能丧失突变的一些致病后果。 Fgf9 可能是由 DICER1 介导的 miRNA 通路直接调控的主要致病基因。在本提案中，我们将： 1) 阐明间充质 FGF 和 Wnt/¿ -连环蛋白信号调节 BMP 通路的 Noggin 表达和活性；2) 在 PPB 小鼠模型中检验 FGF9 是间质增生致病介质的假设；3) 比较 FGF9 和 Wnt/¿ -连环蛋白信号传导以及 Fgf9 和 Dicer1 小鼠模型的 PPB 与早期人类 PPB。