MECHANISMS OF BPD PATHOGENESIS

BPD 发病机制

• 批准号: 8588348
• 负责人: Parviz Minoo Minoo
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588348
• 关键词: Address; Adult; Alveolar; Behavior; Bleomycin; Blood Vessels; Bronchopulmonary Dysplasia; Cell Proliferation; Cells; Chronic lung disease; Consensus; Data; Defect; Development; Ectopic Expression; Employee Strikes; Epithelial; Experimental Models; FGF10 gene; Fibrosis; Genetically Engineered Mouse; Growth Factor; Histologic; Human; Hyperoxia; In Vitro; Infant; Injury; Interruption; Link; Lung; Measures; Mediating; Mesenchymal; Mesenchyme; Modeling; Molecular Genetics; Morphogenesis; Mus; Neonatal; Newborn Animals; PIK3CG gene; Pathogenesis; Pathway interactions; Premature Birth; Premature Infant; Process; Pulmonary Fibrosis; Research Project Grants; Rest; Role; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Stem cells; Testing; Time; Transforming Growth Factor beta; Transgenic Mice; base; in utero; in vivo; in vivo Model; lung development; lung injury; mouse model; overexpression; receptor; research study

Bronchopulmonary Dysplasia or BPD is a chronic lung disease that results from interruption of normal in utero lung development by premature birth. We have shown that bioactive TGFBeta in the lungs of human preterm infants predicts severity of BPD, suggesting a possible role in its pathogenesis and arrested lung development. Another key signaling molecule with suggested role in pathogenesis of BPD is FGF10 which was recently found to be decreased significantly in BPD lungs. Our preliminary studies establish an operational link between FGF10 & TGFBeta through the Pten/PI3k/Akt/Erk pathway. We have further shown that FGF10 can protect lungs from TGFBetainduced fibrosis in mice. This project will use simple genetic and molecular approaches to address the role of TGFBeta & FGF10 in pathogenesis of BPD. The logical basis for the current proposal rests on a number of preliminary, but important data that collectively, support the following overall hypothesis: HYPOTHESIS: We hypothesize that TGFBeta signaling via T¿RII derails lung morphogenesis by inhibiting epithelial progenitor cell proliferation, mediated thru increased Pten, which leads to inhibition of PI3k/Akt/Erk pathway. We further hypothesize that FGF10 can protect the neonatal lung from hyperoxia/TGFBeta-mediated injury & BPD at least in part by countering the inhibitory effect of TGFBeta on the PI3k/Akt/Erk pathway. The following specific aims will test the validity of the above hypothesis Specific Aim 1. To Determine the Precise Pathway via Which TGFBeta Inhibits Epithelial Progenitor Cell Proliferation and Morphogenesis in both in vitro & in vivo Models. The availability of genetically engineered mice offers an unprecedented opportunity to elucidate the precise role of a key target of TGFBeta, Pten, & its signaling target, the PI3k/Akt/Erk pathway in both in vitro & in vivo settings. Specific Aim 2. To determine the Potential Role of TBetaRII in Epithelial & Mesenchymal Compartments of the Lung in Pathogenesis of Hyperoxia-¿Induced Hypoalveolization in Neonatal Mice (The mouse BPD Model). Mice carrying either Epithelial-¿or Mesenchymal-specific deletion of TBetaRII will be exposed to hyperoxia and the process of alveolization will be measured by state-of-the-art technical approaches. Specific Aim 3. To Determine the Role of FGF10 in a Murine Model of Hyperoxia-¿Induced Hypoalveolization. We have shown that mesenchymal deletion of TBetaRII leads to increaseded FGF10. Remarkably regulated ectopic expression of Fgf10 in transgenic mice protects from bleomycin-induced adult lung injury. In this aim, we will test the hypothesis that ectopic Fgf10 also protects from hyperoxia-induced lung injury in neonatal transgenic mice. As in Specific Aim 1, the focus of the mechanisms in this aim will be the PI3k/Akt/Erk pathway.

支气管肺发育不良或BPD是一种慢性肺部疾病，由早产导致宫内肺正常发育中断所致。我们已经证明，人类早产儿肺中具有生物活性的TGFbeta可以预测BPD的严重程度，这表明BPD在其发病机制和肺发育受阻中可能发挥作用。另一个在BPD发病机制中可能起作用的关键信号分子是FGF10，最近发现它在BPD肺组织中显着降低。我们的初步研究通过Pten/PI3K/Akt/Erk通路在FGF10和TGFbeta之间建立了可操作的联系。我们进一步证明，FGF10对TGFBB诱导的小鼠肺纤维化有保护作用。这个项目将使用简单的遗传和分子方法来研究转化生长因子β和转化生长因子10在BPD发病机制中的作用。目前这一提议的逻辑基础是基于一些初步但重要的数据，这些数据共同支持以下总体假设：假设：我们假设TGFbeta信号通过T？RII抑制上皮祖细胞增殖而破坏肺形态发生，通过增加Pten介导，从而抑制PI3K/Akt/Erk通路。我们进一步假设，FGF10至少部分通过拮抗TGFβ对PI3K/Akt/Erk通路的抑制作用而保护新生大鼠肺免受高氧/TGFβ介导的损伤。以下具体目的将检验上述假说的有效性：1.在体外和体内模型中，确定TGFβ抑制上皮祖细胞增殖和形态发生的确切途径。基因工程小鼠的出现为阐明TGFbeta的关键靶点Pten及其信号靶点PI3K/Akt/Erk通路在体外和体内环境中的确切作用提供了前所未有的机会。具体目的2.探讨TBetaRII在高氧致新生小鼠肺低肺泡形成(BPD模型)中的作用。携带上皮性或间叶性TBetaRII特异性缺失的小鼠将暴露在高氧中，肺泡化过程将通过最先进的技术方法进行测量。具体目的3.探讨成纤维细胞生长因子10在高氧性低肺泡形成小鼠模型中的作用。我们已经证明TBetaRII的间质缺失会导致FGF10的增加。显著调控Fgf10在转基因小鼠中的异位表达对博莱霉素诱导的成人肺损伤具有保护作用。为了达到这个目的，我们将检验这一假说，即异位Fgf10也能保护新生转基因小鼠免受高氧诱导的肺损伤。与具体目标1一样，这一目标的机制的重点将是PI3K/Akt/Erk通路。