AUROCRINE/PARACRINE GROWTH FACTORS & LUNG MORPHOGENESIS

肺的分子胚胎学研究可能提供 对肺的分子过程的重要的新的机械见解 疾病 在01-03年的支持期间，我们已经确定， 自分泌/旁分泌信号传导，特别是EGF受体的激活 表皮生长因子受体（EGFR）的EGF，指导胚胎小鼠肺分支形态发生， 化学定义的文化 新的数据显示，EGF和 TGF β信号通路相互作用， 形态发生 假设：TGF β受体介导的信号传导指导早期小鼠 胚胎肺分支形态发生，调节和被调节 EGFR介导的信号传导。 具体目标： 目标1。定义TGF β的发育和时空表达 I和IIR在胚胎肺分支形态发生中的作用 在体内和无血清培养中的细胞分化。 目标2.为了确定TGF β信号转导在调节 胚胎肺分支形态发生和细胞分化 无血清培养。 目标3。确定EGF和TGF之间串扰的分子机制 β信号传导： (i)在胚胎肺分支形态发生中， 无血清培养中的细胞分化， (ii)在原代培养的胚胎肺间充质细胞中， 与MvlLu细胞比较。 目标4。定义TGF β I和II之间的蛋白质-蛋白质相互作用 受体以及下游信号分子。 未来的目标：确定生长因子受体的分子机制 介导的相互作用的信号和转录激活的肺 发育基因 临床相关性：为新方法提供依据， 基于肽生长因子的肺部治疗策略， 改善肺损伤和增强肺修复，特别是在非常 出生时肺发育不完全的未成熟人类婴儿。

Studies of the molecular embryology of the lung are likely to provide significant new mechanistic insights into the molecular processes of lung disease. During Years 01-03 of support, we have established that autocrine/paracrine signalling, specifically activation of EGF receptor (EGFR) by EGF, instructs embryonic mouse lung branching morphogenesis in chemically defined culture. New preliminary data indicate that EGF and TGF beta signalling pathways interact to instruct pulmonary morphogenesis. Hypothesis: TGF beta receptor mediated signalling instructs early mouse embryonic lung branching morphogenesis, modulates and is modulated by EGFR mediated signalling. Specific Aims: Aim 1. To define developmental and temporo-spatial expression of TGF beta I and IIR during embryonic pulmonary branching morphogenesis and cytodifferentiation in vivo and in serumless culture. Aim 2. To determine the function of TGF beta signaling in regulating embryonic pulmonary branching morphogenesis and cytodifferentiation in serumless culture. Aim 3. To define molecular mechanisms of crosstalk between EGF and TGF beta signalling: (i) in embryonic pulmonary branching morphogenesis and cytodifferentiation in serumless culture, (ii) in embryonic pulmonary mesenchymal cells in primary culture with comparisons to MvlLu cells. Aim 4. To define protein-protein interactions between TGF beta I and II receptors as well as downstream signalling molecules. Future Aims: To define molecular mechanisms of growth factor receptor mediated interactive signalling and transcriptional activation of lung developmental genes. Clinical relevance: To provide a rationale for novel approaches to peptide growth factor based pulmonary therapeutic strategies to ameliorate lung injury and augment lung repair, particularly in very immature human infants in whom lung development is incomplete at birth.