AUROCRINE/PARACRINE GROWTH FACTORS & LUNG MORPHOGENESIS

对肺的分子胚胎学的研究可能会提供 对肺的分子过程的重要的新的机械学见解 疾病。在01-03年度的支持期间，我们确立了 自分泌/旁分泌信号，特别是EGF受体的激活 (EGFR)通过EGF，指导胚胎小鼠肺分支形态发生 化学定义的培养。新的初步数据表明，EGF和 转化生长因子β信号通路相互作用指导肺 形态发生。 假设：转化生长因子β受体介导的信号转导早期小鼠 胚胎肺分支形态发生，并受其调控 EGFR介导的信号转导。 具体目标： 目的1.明确转化生长因子β的发育和时空表达 I和IIR在胚胎肺分支形态发生和发育中的作用 体内和无血清培养条件下的细胞分化。 目的2.确定转化生长因子β信号在调控中的作用 胚胎肺分支形态发生和细胞分化的研究 无血清文化。 目的3.明确表皮生长因子与转化生长因子相互作用的分子机制 Beta信令： (I)胚胎肺分支形态发生和 无血清培养中的细胞分化， (Ii)原代培养的胚胎肺间充质细胞 与MvlLu细胞的比较。 目的4.确定转化生长因子β1和转化生长因子2之间的蛋白质-蛋白质相互作用 受体以及下游的信号分子。 未来目标：确定生长因子受体的分子机制 介导的相互作用信号和肺转录激活 发育基因。 临床相关性：为新的治疗方法提供理论基础 基于多肽生长因子的肺部治疗策略 改善肺损伤和加强肺修复，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.