Regulation of Branching Morphogenesis of Salivary Gland

描述：细胞内信号转导通路由生长因子和 已知整合素在以下几个细胞中驱动发育和分化 纸巾。然而，目前还没有关于这种机制的信息 发育的唾液腺。早先公布的和初步数据显示 表皮生长因子受体(EGFR)和 含有α6亚基的整合素是分支形态发生所必需的 胎鼠颌下腺(SMG)。几种细胞内途径 已经定义了由EGFR和/或整合素激活。最具特色的 信号通路通过RAS/MEK/ERK级联，或磷脂酶CGamma1 (PLCGamma1)，或磷脂酰肌醇-3-激酶(PI3K)。后两种酶 激活蛋白激酶C(PKC)。初步研究已经表明 Ras/MEK/ERK信号转导通路是细胞分枝形态发生所必需的。 SMG的活性因胎龄不同而不同。一种用于分析的系统 FULL条件下分离培养的胎儿SMG上皮的分枝形态发生 使用Matrigel定义的条件和已知的EGF数量最近成为 可用。主要的假说是年龄相关的变异 由EGFR和BMP激活的三条主要信号通路的活性 整合素通过动态调控影响SMG的发育过程 ERK和PKB的正信号通路，由负信号平衡 PKC。有计划通过以下方式检验这一假设：具体目标1：建立 多种PKC对胎儿SMG中EGFR的表达具有负性调节作用。具体目标2： 为了证明通过PLCGamma1和PI3K的信号在 分枝形态发生。具体目标3：鉴定PKC同工酶 调节分枝形态发生。具体目标4：界定监管 EGFR和含有α6整合素的整合素在特定信号转导中的作用 控制SMG分枝形态发生的成分。建议进行的研究 对于理解正常的发育机制将具有重要意义 定义导致先天性畸形或变形的功能障碍 导致癌症，并促进再生和组织的努力 唾液腺工程学。

DESCRIPTION: Intracellular signaling cascades activated by growth factors and integrins are known to drive development and differentiation in several tissues. Nevertheless, no information is available about such mechanisms in developing salivary glands. The earlier published and preliminary data show that engagement of both the epidermal growth factor receptor (EGFR) and integrins containing the alpha6-subunit are needed for branching morphogenesis of the fetal mouse submandibular gland (SMG). Several intracellular pathways activated by EGFR and/or integrins have been defined. The best characterized pathways signal via the RAS/MEK/ERK cascade, or phospholipase Cgamma1 (PLCgamma1), or phosphoinositol-3-kinase (PI3K). The latter two enzymes activate protein kinase C (PKC). The preliminary studies have already shown that the RAS/MEK/ERK pathway is necessary for branching morphogenesis of the SMG, and that its activity varies with fetal age. A system for analysis of branching morphogenesis of isolated fetal SMG epithelium cultured under fully defined conditions with Matrigel and know amounts of EGF has recently become available. The Major Hypothesis is that age-dependent variations in the activity of the three major signaling pathways triggered by EGFR and by integrins affect the course of development of the SMG by a dynamic regulatory circuit of positive signaling by ERK and PKB, balanced by negative signaling by PKC. There are plans to test this hypothesis by: Specific Aim 1: To establish that various PKC negatively regulate the EGFR in the fetal SMG. Specific Aim 2: To demonstrate that signaling via PLCgamma1 and PI3K have essential roles in branching morphogenesis. Specific Aim 3: To identify the PKC isozymes that regulates branching morphogenesis. Specific Aim 4: To define the regulatory roles of the EGFR and of the alpha6-containing integrins on specific signaling components controlling branching morphogenesis of the SMG. The proposed studies will have significance for understanding normal developmental mechanisms, for defining dysfunction leading to congenital malformations or to transformations resulting in carcinomas, and for advancing efforts on regeneration and tissue engineering of salivary glands.