Interactive Mediators of Injury & Development

描述（由申请人提供）：支气管肺发育不良（BPD）的特征是肺泡发育不全，被认为是由远端肺形态发生停滞引起的。目前，炎症和促纤维化生长因子，如TGF-β，被认为是损伤的主要原因。在人类早产新生儿中，肺TGF-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TGF-β的作用：假设：损伤的介导剂，特别是TGF-β 1激活的SMAD 3干扰正常的发育途径并导致BPD的发病机制。为了验证上述假设，我们提出了三个具体目标： 具体目标1.确定新生Smad 3（-/-）小鼠是否以及在多大程度上免受高氧或病毒传递的TGF-β 1诱导的肺泡发育不全的影响？ 具体目标2。为了确定是否胚胎Smad 3（-/-）肺保护免受TGF-β 1的病理作用？ 具体目标3。为了确定是否有条件的Smad 3过表达导致结构异常和无效或部分SP-B缺乏症在围产期和出生后的转基因小鼠？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。该项目提供了一个独特的机会来精确阐明TGF-β作为已知的损伤介质，如何通过SMAD 3影响关键形态调节转录因子（如NKX2.1）的正常功能来破坏肺形态发生。

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.