REGULATION OF BRANCHING MORPHOGENESIS OF SALIVARY GLAND

描述(改编自申请人的摘要)：上皮- 间充质(E-M)相互作用在骨肉瘤发生发展中的主要作用 上皮性器官。大多数对这些E-M的调解机制的分析 相互作用主要集中在细胞外基质的成分上。 (ECM)。细胞黏附分子研究的最新进展 现在提供了一个机会来研究实际的上皮细胞的作用 这些相互作用中的细胞。整合素构成一类细胞 作为特定ECM组件的受体的表面蛋白。 胎鼠的颌下腺(SMG)表现出良好的 研究上皮-间充质相互作用的特征化系统 在体内和体外。已发表的关于PI的研究和初步数据 提示EGF和转化生长因子α促进SMG的发生发展。 培养，而EGF受体的抑制剂(Tyrphostin)则减少 SMG的成长和发展。调查人员推测，这些 生长因素可能通过调节影响SMG的发育 整合素在上皮细胞上的表达，这随后决定了 它们在发育过程中与间充质相互作用的性质。 为了解决这一假设，我们提出了三个具体目标： 1)鉴定整合素和细胞外基质成分的表达 在SMG的体内和体外发育过程中，并建立是否 这些分子的扰动干扰了正常的SMG发育。 2)研究表皮生长因子和转化生长因子α在SMG发生发展中的作用 在体外，并确定这些生长因子是否调节 整合素及其ECM配体。 3)确定EGF和转化生长因子α是否为血管紧张素转换酶的生理调节因子 SMG的发育并确定它们是否由间充质细胞产生 SMG的细胞。 这些研究的结果有望增进对SMG的了解 发展动态，并潜在地洞察到对方 SMG上皮间充质相互作用对过程的影响 创面愈合、转移与先天性心脏病的发生 畸形。

DESCRIPTION (Adapted from the Applicant's Abstract): Epithelial- mesenchymal (E-M) interactions play primary roles in development of epithelial organs. Most analyses of mechanisms mediating these E-M interactions have focused on components of the extracellular matrix (ECM). Recent advances in our understanding of cell adhesion molecules now afford an opportunity to examine the role of the actual epithelial cells in these interactions. Integrins constitute a class of cell surface proteins that serve as receptors for specific ECM components. The submandibular gland (SMG) of the fetal mouse presents a well characterized system to study epithelial-mesenchymal interactions both in vivo and in vitro. Published studies and preliminary data of the PI indicate that EGF and TGF alpha promote development of the SMG in culture, while an inhibitor of the EGF receptor (tyrphostin) diminishes SMG growth and development. The investigators hypothesize that these growth factors may be influencing SMG development by regulating expression of integrins on epithelial cells, which subsequently dictates the nature of their interactions with the mesenchyme during development. Three Specific Aims are proposed to address this hypothesis: 1) To characterize the expression of integrins and ECM components during development of the SMG in vivo and in vitro and to establish if perturbations of these molecules interferes with normal SMG development. 2) To characterize the effects of EGF and TGF alpha on SMG development in vitro and to determine if these growth factors regulate expression of integrins and their ECM ligands. 3) To establish whether EGF and TGF alpha are physiologic regulators of SMG development and to determine whether they are produced by mesenchymal cells of the SMG. Results of these studies are expected to enhance the understanding of SMG developmental dynamics and potentially yield insight into the other processes impacted on by SMG epithelial mesenchymal interactions such as wound healing, metastasis and the genesis of congenital malformations.