Interactive Mediators of Injury & Development

伤害的互动调解者

• 批准号: 6722480
• 负责人: Parviz Minoo Minoo
• 金额: $ 32.44万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722480
• 关键词: biological signal transduction; bronchopulmonary dysplasia; disease /disorder etiology; embryo /fetus; gene expression; gene induction /repression; genetically modified animals; histogenesis; hyperoxia; infant animal; laboratory mouse; lung development; pathologic process; transcription factor; transfection /expression vector; transforming growth factors

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.

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所致。目前，炎症和促纤维化生长因子（例如 TGF-β）被认为是损伤的主要原因。在人类早产儿中，肺 TGF-β 与 BPD 的严重程度相关。当前的项目建议在以下假设的背景下检查 TGF-β 的作用： 假设：损伤介质，特别是 TGF-β1 激活的 SMAD3 干扰正常发育途径并导致 BPD 的发病机制。为了检验上述假设，我们提出三个具体目标： 具体目标 1. 确定新生 Smad3(-/-) 小鼠是否以及在多大程度上受到保护，免受高氧或病毒传递的 TGF-β1 诱导的肺泡发育不全？ 具体目标 2. 确定外植的胚胎 Smad3(-/-) 肺是否能免受 TGF-β1 的病理作用？ 具体目标 3. 确定 Smad3 的条件性过度表达是否会导致围产期和产后转基因小鼠的结构异常以及 SP-B 完全或部分缺乏？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准确阐明 TGF-β 作为一种已知的损伤介质，如何通过 SMAD3 影响关键形态调节转录因子（如 NKX2.1）的正常功能，从而破坏肺形态发生。