TGF BETA3 IN LUNG MORPHOGENESIS, INJURY AND REPAIR

转化生长因子（TGF）家族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 特异于TGF-β 3，我们产生了TGF-β 3无效突变小鼠。 这些 Shoul独特的表型特征仅限于迟发性肺动脉高压 发育和腭裂，出生后不久死亡。 肺 出现原始的肺泡化减少。 的风险 新生儿肺部疾病 这些数据表明了重要的作用 TGF-β在围产期肺发育中的作用，我们假设 TGF-β 3参与肺部疾病的病理生物学。 我们提出 为了进一步确定TGF-β的时空影响是否 对肺发育的影响，从无效突变体中明显可见，主要发生在 早期胚胎与晚期胎儿的阶段， 影响是对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 TGF-β 3通过其调节肺发育和肺修复 损伤，采用代表性差异分析比较我们的 TGF-β 3无效突变体和野生型的过表达子。 的影响 TGF-β 3过表达对肺器官发生和修复的影响 与已知的TGF-β 1的有害作用相比， 使用过表达TGF-β 3的转基因小鼠， TGF-β 3启动子。 TGF-β 3缺乏对出生后 肺发育和肺修复对实验诱导的 将在TGF-β 3无效突变体中评估肺损伤，其中 TGF-β 3的产生可以根据需要开启和关闭。 我们 实验将确定TGF-β 3在两个肺中的特定作用， 发育和修复，包括新生儿慢性 使用独特的体内小鼠模型。 生成的数据将 对实现这一长期目标具有重要意义 开发新生儿疾病合理治疗方案 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.