Excess TGF beta in neonatal lung injury and repair

描述（由申请人提供）：假设：TGF β信号通路可能是介导新生儿肺损伤对肺泡形成和气体交换的负面影响的最终共同通路。 目标1。候选基因诱导：以确定新生小鼠肺中新生高氧和/或LP 5内毒素对TGF β配体、同源受体和同源Smad（2、3和4）表达的时间和空间特异性表达和活性的影响。目标2.候选基因功能：使用重组腺病毒载体比较新生儿高氧和/或LP 5内毒素相对于局部过表达IL 1-β或TNF-α和TGF-β 1的影响，以确定它们中哪一个也通过消除肺泡化而表型化BPD。目标3. Smad 3作为一个共同的下游基因：为了发现新生儿高氧和/或LPS内毒素损伤的影响，新生儿肺中的IL 1 β、TNF α和/或TGF β 1信号传导通过共同的TGF-α/Smad 3信号传导途径，使用Smad 3敲除小鼠作为测试模型。目标4。防护：以确定是否可以使用表达核心蛋白聚糖或Smad 7的重组病毒阻断或改善TGF-β途径上游或下游的新生儿高氧和/或LP 5内毒素损伤对肺泡形成的负面后遗症。 健康意义：我们假设阻断TGF β信号传导的关键上游诱导物、正确调节TGF β信号传导和/或抑制TGF β的下游作用可以预防或改善肺泡发育不全/BPD。

DESCRIPTION (provided by applicant): Hypothesis: The TGFbeta signaling pathway may function as a final common pathway to mediate the negative impact of neonatal lung injury on alveolar formation and gas exchange. Aim 1. Candidate gene induction: to determine the impact of neonatal hyperoxia and/or LP5 endotoxin, on time and space-specific expression and activity of TGFbeta ligand, cognate receptor and cognate Smad (2,3 and 4) expression in neonatal mouse lung. Aim 2. Candidate gene function: to compare the impact of neonatal hyperoxia and/or LP5 endotoxin, versus local overexpression of IL1-beta, or TNF-alpha, with that of TGF-beta1 using recombinant adenoviral vectors to determine which of them also phenocopies BPD by abrogation of alveolarization. Aim 3. Smad3 as a common downstream gene: to discover which effects of neonatal hyperoxia and/or LPS endotoxin injury, IL1beta, TNFalpha, and/or TGFbeta1 signaling in neonatal lung are transduced through a common TGF-alpha/Smad3 signaling pathway, using the Smad3 null mouse as a test model. Aim 4. Protection: to determine whether the negative sequelae of neonatal hyperoxia and/or LP5 endotoxin injury on alveolar formation can be blocked or ameliorated, either upstream or downstream within the TGF-beta pathway using recombinant viruses expressing Decorin or Smad7. Health Significance: we postulate that blocking key upstream inducers of TGFabeta signaling, correctly modulating TGFbeta signaling and/or inhibiting the downstream effects of TGFbeta could prevent or ameliorate alveolar hypoplasia/BPD.