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MECHANISMS OF BPD PATHOGENESIS

BPD 发病机制

基本信息

批准号：
8776327
负责人：
Parviz Minoo Minoo
金额：
$ 40.45万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8776327
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

项目摘要

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，是由于早产导致子宫内肺正常发育中断而引起的。我们已经证明，人类早产儿肺部的生物活性TGF β可预测BPD的严重程度，这表明其可能在其发病机制和肺部发育受阻中发挥作用。另一个在BPD发病机制中发挥作用的关键信号分子是FGF 10，最近发现它在BPD肺部显着减少。我们的初步研究通过Pten/PI 3 k/Akt/Erk途径建立了FGF 10和TGF β之间的操作联系。我们进一步证明了FGF 10可以保护肺免受TGF β的影响，诱导小鼠纤维化。该项目将使用简单的遗传和分子方法来解决TGF β和FGF 10在BPD发病机制中的作用。目前建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TGF β通过T <$RII信号传导通过抑制上皮祖细胞增殖而破坏肺形态发生，通过增加Pten介导，这导致PI 3 k/Akt/Erk通路的抑制。我们进一步假设，FGF 10可以保护新生儿肺免受高氧/TGF β介导的损伤和BPD，至少部分是通过对抗TGF β对PI 3 k/Akt/Erk通路的抑制作用。以下具体目标将检验上述假设具体目标1的有效性。在体外和体内模型中确定TGF β抑制上皮祖细胞增殖和形态发生的精确途径。基因工程小鼠的可用性提供了前所未有的机会来阐明TGF β的关键靶标Pten及其信号传导靶标PI 3 k/Akt/Erk通路在体外和体内环境中的确切作用。具体目标2。确定TBetaRII在新生小鼠（小鼠BPD模型）中高氧诱导肺泡形成的发病机制中在肺上皮和间质复合物中的潜在作用。将携带上皮特异性或间质特异性TBetaRII缺失的小鼠暴露于高氧，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FGF 10在高氧诱导的肺泡发育不良小鼠模型中的作用。我们已经表明，间充质TBetaRII缺失导致FGF 10增加。Fgf 10在转基因小鼠中的显著调节的异位表达保护博来霉素诱导的成年肺损伤在这个目标中，我们将测试的假设，异位Fgf 10也保护新生转基因小鼠高氧诱导的肺损伤。与具体目标1中一样，该目标中的机制的焦点将是PI 3 k/Akt/Erk途径。