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: 8371642
• 负责人: David M Ornitz
• 金额: $ 52.07万
• 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/8371642
• 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. PUBLIC HEALTH RELEVANCE: Lung disease is the fourth leading cause of death and disability in the United States. The etiology of lung disease often begins during embryonic development or early in life. To understand the pathogenesis of genetic, developmental, and acquired lung disease, to develop diagnostic criteria for these diseases, and to develop rational therapies, knowledge of the molecular, cellular and developmental mechanisms that regulate lung development is necessary. This proposal will focus on developmental mechanisms that involve Fibroblast Growth Factor 9, a signaling molecule that is essential for lung development and implicated as a pathogenic mediator of pleuropulmonary blastoma, a rare pediatric lung cancer.

描述(申请人提供：肺部疾病的起源通常始于发育阶段。解开调节发育的复杂机制对于理解发育性、遗传性和获得性肺部疾病的发病机制至关重要。这项建议主要围绕成纤维细胞生长因子9(FGF9)信号调节肺发育的机制展开。FGF9在肺上皮和间皮细胞中表达，在肺上皮细胞的调节中起主要作用，其次是直接和间接调节作用。我们发现了一个涉及间充质成纤维细胞生长因子受体(FGFR)和Wnt/β-catenin信号转导的前馈调控网络。在这项提案首次提交以来发表的数据中，我们表明在体内，成纤维细胞生长因子和Wnt/β-连环蛋白通路都发挥抑制Noggin的作用。这一发现将间充质的成纤维细胞生长因子-Wnt/β-连环蛋白信号与调节上皮生长和分化的BMP通路结合在一起。另一种洞察发育机制的方法是研究癌症的发病机制，这种疾病通常采用胚胎调节机制。肺间充质中的FGF9信号与人类肺部疾病之间的潜在联系涉及可遗传的儿童肺癌综合征，胸膜肺母细胞瘤(PPB)。PPB很有趣，因为它起源于胚胎未固定的肺间充质细胞。诱导过表达FGF9的小鼠胚胎肺出现间质增生，其组织学与I型PPB相似，提示FGF9可能参与了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。初步和已发表的数据显示，Dicer1消融发育中的肺上皮类似于PPB的早期囊性阶段。具有DICER1突变的PPB肿瘤的免疫组织化学研究经常显示DICER1在肺上皮细胞中的表达降低。这些观察结果提示了一种解释PPB发病机制的模型，在该模型中，经DICER1处理的上皮miRNAs减少导致上皮基因(S)过表达和一种因子(S)的产生，该因子刺激邻近间充质的增殖，使间充质易于肿瘤转化。初步数据提供的证据表明，上皮来源的FGF9参与了DICER1功能丧失突变的一些致病后果。我们推测Fgf9可能是一个主要的致病基因，直接受DICER1介导的miRNA途径调控。在这个方案中，我们将：1)阐明间充质成纤维细胞生长因子和Wnt/β-catenin信号调节BMP途径Noggin表达和活性的机制；2)在PPB的小鼠模型中验证FGF9是间充质增生的致病介质的假设；3)比较FGF9和Wnt/β-catenin信号以及Fgf9和Dicer1小鼠PPB模型与早期人类PPB的肺间充质转录格局。 公共卫生相关性：在美国，肺部疾病是导致死亡和残疾的第四大原因。肺部疾病的病因通常始于胚胎发育或生命早期。为了了解遗传性、发育性和获得性肺部疾病的发病机制，制定这些疾病的诊断标准，并开发合理的治疗方法，需要了解调节肺发育的分子、细胞和发育机制。这项提案将侧重于涉及成纤维细胞生长因子9的发育机制，成纤维细胞生长因子9是一种对肺发育至关重要的信号分子，可能是一种罕见的儿童肺癌--胸膜肺母细胞瘤的致病介质。