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: 8704993
• 负责人: David M Ornitz
• 金额: $ 49.76万
• 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/8704993
• 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; 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 regeneration; 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（应用程序提供：肺部疾病的起源经常在发育过程中开始。阐明调节发育的复杂机制对于理解发育，遗传和肺病的发病机理至关重要。该建议集中于成纤维细胞生长因子9（FGF9）信号调节肺部的作用和MES EPERIUM的作用。间质和二次直接和间接作用在肺上皮的调节中。这一发现与BMP途径调节上皮生长和分化的BMP途径的间充质FGF-WNT/�-Catenin信号传导，以深入了解开发机制，这是一种疾病，这种疾病通常是对胚胎调节机制的选择。肺间隙中FGF9信号传导与人类肺部疾病之间的潜在联系涉及可遗传的小儿肺癌综合征，胸膜炎胸膜炎（PPB）。 PPB很有趣，因为它是由胚胎未施加的肺间充质细胞引起的。诱导过表达FGF9的小鼠胚胎肺具有模仿I型PPB的组织学发展间充质增生，这表明FGF9可能与PPB的发病机理有关。将PPB的遗传起源映射到microRNA（miRNA）加工基因DICER1中的功能丧失突变。初步和发布的数据表明，DICER1在发展肺上皮模仿PPB的早期囊性阶段时消融。 DICER1突变的PPB肿瘤的免疫组织化学研究通常显示出肺上皮的DICER1表达的改善。这些观察结果提出了一个模型来解释PPB的发病机理，在这种模型中，通过DICER1处理的改进的上皮miRNA导致上皮基因过度表达和产生因子​​（S）的产生，从而刺激了邻近的间质的增殖，使Mesecthyme倾向于造成膜层转化。初步数据提供了证据表明，在介导DICER1中功能丧失突变的某些致病后果时，实现上皮衍生的FGF9。我们假设FGF9可能是由DICER1介导的miRNA途径直接调节的主要致病基因。在此提案中，我们将：1）阐明间充质FGF和Wnt/¿-Catenin信号传导调节BMP途径的Noggin表达和活性的机制； 2）检验假设FGF9是PPB小鼠模型中间充质增生的致病介质； 3）比较由FGF9和Wnt/® -Catenin信号传导以及由FGF9和DICER1小鼠模型的肺间充质转录景观与早期阶段人PPB进行比较。