LUNG ALVEOLAR EPITHELIAL CELL DIFFERENTIATION

已知间充质-上皮细胞的相互作用是 胎儿肺的形态发生。间充质-上皮的相互作用可能 部分是由细胞外基质介导的。我们假设 细胞外基质的组成和结构的变化 先于，否则伴随着胎肺的分化 肺泡上皮细胞。 最近，转化生长因子β(TGFbeta)，一种生长因子， 已知可调节细胞外基质的组成，已被证明 抑制SP-A的表达，这是一种与表面活性物质相关的蛋白 在分化的II型细胞中合成。相反，表皮生长 另一种已知可调节细胞外基质的生长因子--表皮生长因子(EGF) 产生，增加SP-A的表达，刺激肺 成熟。我们建议本地化并评估以下水平的变化 胎盘发育过程中TGFβ和EGF及其同系物TGFα的表达 兔肺在体成熟的形态和分子生物学研究 技巧。我们将描述这些增长因素对 兔细胞外基质的结构和组成 外植体中的分化。我们之前已经证明了胎儿的肺 肺泡上皮细胞培养时纤维连接蛋白浓度升高 差异化。我们建议扩大这些研究的范围，确定 转化生长因子β和表皮生长因子对纤维连接蛋白基因表达的影响 纤维连接蛋白受体的mRNA水平。最后，我们建议 评价细胞外信使核糖核酸对纤维连接蛋白受体的影响。 最后，我们建议评估细胞外基质的作用。 纯化的II型细胞维持分化的成分 维持在单层培养中。我们将把细胞外基质- 诱导的细胞骨架和细胞形状的变化到II型的程度 细胞在体外分化，特别是在表达方面 SP-A的。 因此，我们将记录两个基因的分布、水平和作用 胎肺组织中的生长因子TGFβ和EGF。我们假设 这些生长因子影响肺的机制之一 成熟涉及到对He的组成和结构的调节。 细胞外基质。因此，我们将记录这些影响 生长因子对细胞外基质成分代谢的影响。这个 我们的研究结果将增加对人的作用的认识 细胞外基质在细胞分化调控中的作用 生长因子在调节胎肺发育中的作用。

Mesenchymal-epithelial interactions are known to be required for the morphogenesis of the fetal lung. Mesenchymal-epithelial interactions may be mediated, in part, by the extracellular matrix. We hypothesize that changes in the composition and structure of the extracellular matrix precede, or else are concomitant with the differentiation of fetal lung alveolar epithelial cells. Recently, transforming growth factor beta (TGFbeta), a growth factor that is known to regulate extracellular matrix composition, has been shown to inhibit the expression of SP-A, a surfactant-associated protein that is synthesized in differentiated type II cells. Conversely, epidermal growth factor, (EGF), another growth factor known to regulate extracellular matrix production, increases the expression of SP-A and stimulates lung maturation. We propose to localize and evaluate changes in the levels of TGFbeta and EGF, or its homologue, TGFalpha, during the course of fetal rabbit lung maturation in vivo using morphological and molecular biology techniques. We will characterize the effects of these growth factors on the structure and composition of the extracellular matrix in rabbit differentiation in the explants. We have shown previously that fetal lung fibronectin concentrations increase at the time of alveolar epithelial cell differentiation. We propose to extend these studies by determining the effects of TGFbeta and EGF on the levels of fibronectin mRNA as well as on the levels of mRNA for the fibronectin receptor. Finally, we propose to evaluate the effects of extracellular of mRNA for the fibronectin receptor. Finally, we propose to evaluate the effects of extracellular matrix components on the maintenance of differentiation in purified type II cells maintained in monolayer culture. We will relate extracellular matrix- induced changes in the cytoskeleton and cell shape to the degree of type II cell differentiation in vitro, in particular with respect to the expression of SP-A. Thus, we will document the distribution, levels of mRNA, and actions of two growth factors TGFbeta and EGF, in fetal lung tissue. We hypothesize that one of the mechanisms by which these growth factors act to influence lung maturation involves the regulation of the composition and structure of he extracellular matrix. Therefore, we will document the effects of these growth factor on the metabolism of extracellular matrix components. The results of our studies will increase knowledge concerning the role of the extracellular matrix in the regulation of cell differentiation a well as the role of growth factors in the regulation of fetal lung development.