Interactive Mediators of Injury & Development

描述(申请人提供)：支气管肺发育不良，BPD，以肺泡发育不良为特征，被认为是由于远端肺形态发生受阻所致。目前，炎症和促纤维化生长因子，如转化生长因子-β，被认为是损伤的主要原因。在人类早产儿中，肺转化生长因子-β与BPD的严重程度相关。目前的项目建议在以下假设的背景下检查转化生长因子-β的作用：假设：损伤的介质，特别是转化生长因子-β1激活的Smad3干扰正常的发育途径，导致BPD的发病。为了验证上述假设，我们提出了三个具体目标： 具体目的1.确定新生Smad3(-/-)小鼠是否受到高氧或病毒传递的转化生长因子-β1诱导的肺泡发育不良的保护，以及在多大程度上受到保护？具体目的2.确定移植的胚胎SMAD3(-/-)肺是否具有抗转化生长因子-β1的病理作用？ 具体目的3.确定Smad3的条件性过表达是否会导致围产期和出生后转基因小鼠的结构异常和SP-B缺失或部分缺失？意义：损伤和正常肺形态发生之间的相互作用被认为是BPD的病因。这个项目提供了一个独特的机会来精确地阐明转化生长因子-β作为已知的损伤介质，如何通过Smad3影响关键的形态调节转录因子如Nkx2.1的正常功能来扰乱肺的形态发生。

DESCRIPTION (provided by applicant): Bronchopulmonary dysplasia, BPD, is characterized by alveolar hypoplasia, thought to result from arrested distal lung morphogenesis. Currently, inflammation and pro-fibrotic growth factors, such as TGF-beta, are deemed as major causes of injury. In human premature neonates, lung TGF-beta correlates with severity of BPD. The current project proposes to examine the role of TGF-beta within the context of the following hypothesis: Hypothesis: Mediators of injury and in particular the TGF-beta1-activated SMAD3 interfere with normal developmental pathways & result in pathogenesis of BPD. To test the above hypothesis, we propose three Specific Aims: Specific aim 1. To determine whether, and to what extent, neonatal Smad3(-/-) mice are protected against hyperoxia-, or virally delivered TGF-beta1-induced alveolar hypoplasia? Specific aim 2. To determine whether explanted embryonic Smad3(-/-) lungs are protected against pathological role of TGF-beta1? Specific aim 3. To determine whether conditional overexpression of Smad3 causes structural abnormalities and null or partial SP-B deficiency in perinatal and postnatal transgenic mice? Significance: Interplay between injury and normal lung morphogenesis is thought to be etiologic of BPD. This project presents a unique opportunity to elucidate precisely how TGF-beta, as a known mediator of injury, disrupts lung morphogenesis by affecting, through SMAD3, the normal function of key morphoregulatory transcription factors such as NKX2.1.