MECHANISMS OF BPD PATHOGENESIS

BPD 发病机制

• 批准号: 8403668
• 负责人: Parviz Minoo Minoo
• 金额: $ 38.94万
• 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/8403668
• 关键词: Address; Adult; Alveolar; Arts; Behavior; Bleomycin; Blood Vessels; Borderline Personality Disorder; 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; abstracting; base; in utero; in vivo; in vivo Model; lung development; lung injury; mouse model; overexpression; receptor; research study

ABSTRACT 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 TGF-beta‐induced 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/TGF-mediated injury & BPD at least in part by countering the inhibitory effect of TGF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 TGF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 TGF, 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.

摘要 支气管肺发育不良（BPD）是一种慢性肺部疾病，是由于早产导致子宫内肺部正常发育中断所致。我们已经证明，人类早产儿肺部中的生物活性 TGFbeta 可以预测 BPD 的严重程度，这表明其可能在其发病机制中发挥作用并阻碍肺部发育。另一个在 BPD 发病机制中发挥作用的关键信号分子是 FGF10，最近发现 FGF10 在 BPD 肺部显着减少。我们的初步研究通过 Pten/PI3k/Akt/Erk 通路建立了 FGF10 和 TGFbeta 之间的操作联系。我们进一步表明，FGF10 可以保护小鼠肺部免受 TGF-β 诱导的纤维化。该项目将使用简单的遗传和分子方法来研究 TGFbeta 和 FGF10 在 BPD 发病机制中的作用。当前提议的逻辑基础依赖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：我们假设通过 TRII 的 TGFbeta 信号转导通过抑制上皮祖细胞增殖来破坏肺形态发生，而上皮祖细胞增殖是通过 Pten 增加介导的，从而导致 PI3k/Akt/Erk 通路的抑制。我们进一步假设 FGF10 至少部分通过对抗 TGF 对 PI3k/Akt/Erk 通路的抑制作用来保护新生儿肺免受高氧/TGF 介导的损伤和 BPD。以下具体目标将检验上述假设的有效性 具体目标 1. 在体外和体内模型中确定 TGF抑制上皮祖细胞增殖和形态发生的精确途径。基因工程小鼠的出现提供了前所未有的机会来阐明 TGF、Pten 及其信号传导靶点 PI3k/Akt/Erk 通路的关键靶点在体外和体内环境中的精确作用。具体目标 2. 确定 TbetaRII 在肺上皮和间质室中在新生小鼠高氧诱导的肺泡化低下发病机制中的潜在作用（小鼠 BPD 模型）。携带上皮或间充质特异性 TbetaRII 缺失的小鼠将暴露于高氧环境，并通过最先进的技术方法测量肺泡化过程。具体目标 3. 确定 FGF10 在高氧诱导的肺泡减少小鼠模型中的作用。我们已经证明，TbetaRII 的间充质缺失会导致 FGF10 增加。转基因小鼠中 Fgf10 的异位表达受到显着调节，可防止博来霉素诱导的成年肺损伤。为此，我们将检验异位 Fgf10 也能保护新生转基因小鼠免受高氧诱导的肺损伤的假设。与具体目标 1 一样，该目标的机制重点是 PI3k/Akt/Erk 通路。