TGF BETA3 IN LUNG MORPHOGENESIS, INJURY AND REPAIR

转化生长因子家族的成员是关键的细胞因子 参与组织形态发生和修复。定义关键功能 针对转化生长因子-β3，我们产生了转化生长因子-β3缺失突变小鼠。这些 应将独特的表型特征局限于迟发性肺病 发育和腭裂，并在出生后不久死亡。肺 看起来原始，肺泡化减少。存在以下风险 发展为新生儿肺部疾病。这些数据表明一个重要的角色 对于围产期肺发育中的转化生长因子-β，我们假设 转化生长因子-β3参与了肺部疾病的病理生物学过程。我们建议 为了进一步确定转化生长因子-β的时空影响 从零突变中明显看出的肺发育主要发生在 早期胚胎阶段与晚期胚胎阶段以及原发阶段 影响的是上皮或间充质中的基因表达。 候选基因将在分子信号通路中被确定 转化生长因子-β3通过其调节肺发育和肺修复 伤害，使用代表性差异分析比较我们的 转化生长因子-β3缺失突变体和过表达野生型。的效果 转化生长因子-β3过表达对肺器官发生和修复的影响 研究，与已知的转化生长因子-β1的有害作用相比， 利用可严格调控的转基因小鼠高表达转化生长因子-β3 转化生长因子-β3启动子。转化生长因子-β3缺失对产后的影响 肺发育和肺修复对实验诱导的反应 肺损伤将在转化生长因子-β3缺失突变体中进行评估，在 可根据需要开启和关闭转化生长因子-β3的生产。我们的 实验将确定转化生长因子-β3在两个肺中的具体作用 发育和修复，包括新生儿慢性疾病的发展 肺部疾病采用独特的活体小鼠模型。生成的数据将 对实现这一长期目标具有重要意义 发展合理治疗新生儿的计划项目 肺部疾病。

Members of the transforming growth factor (TGF) family are key cytokines involved in tissue morphogenesis and repair. Todefine key functions specific to TGF-beta3, we generated TGF-beta3 null mutant mice. These shoul unique phenotypic features restricted to delayed pulmonary development and a cleft palate and die shortly after birth. Lungs appeared primitive with decreased alveolarization. The risk for developing neonatal lung disease. These data indicate an important role for TGF-beta in perinatal lung deelopment and we hypothesize that TGF-beta3 is involved in the pathobiology of lung disease. We propose to further determine whether the temporo-spatial influence of TGF-beta on lung development evident from the null mutant occurs primarily during the early embryonic versus late fetalstages and whether the primary effects are on gene expression in the epithelium or mesenchyme. Candidate genes will be identified in the molecular signaling pathways through which TGF-beta3 regulates lung development and repair of lung injury, using representational difference analysis for cocmparing our TGF-beta3 null mutants and overexpressors to wild type. Effects of TGF-beta3 overexpression on lung organogenesis and repair will be investigated, as compared to the known deleterious effects of TGF-beta1, using transgenic mice overexpressing TGF-beta3 froma tightly regulatable TGF-beta3 promoter. The consequences of TGF-beta3 absence on postnatal lung development and lung repair in response to experimentally elicited pulmonary injury will be assessed in TGF-beta3 null mutants, in which the production of TGF-beta3 can be switched on and off as required. Our experiments will identify specific roles of TGF-beta3 in both lung development and repair including the development of neonatal chronic lung disease using unique in vivo mouse models. The data generated will be of importance towards the realization of the long-termgoals of this Program Project of developing rational therapeutics against neonatal pulmonary disease.