Regulation of Branching Morphogenesis of Salivary Gland

描述：细胞内信号级联被生长因子激活， 已知整联蛋白驱动几种细胞的发育和分化， 组织中然而，没有关于这些机制的资料， 正在发育的唾液腺此前公布的初步数据显示， 表皮生长因子受体（EGFR）和 含有α 6亚基的整联蛋白是分枝形态发生所必需的 胎鼠下颌下腺（SMG）。几种细胞内途径 已经定义了由EGFR和/或整联蛋白激活的细胞因子。最佳表征的 信号通路通过RAS/MEK/ERK级联或磷脂酶Cgamma1 （PLC γ 1）或磷酸肌醇-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通路是细胞分支形态发生所必需的。 SMG的活性随胎龄而变化。一种用于分析 完全培养的胎儿SMG上皮的分支形态发生 使用Matrigel和已知量的EGF的定义条件最近已成为 available.主要的假设是，年龄依赖性的变化， 由EGFR和EGFR激活的三种主要信号通路的活性 整联蛋白通过动态调节SMG的发育过程， ERK和PKB的正信号传导回路，由 蛋白激酶C具体目标1：确定 多种PKC负调控胎儿SMG中EGFR的表达。具体目标二： 为了证明通过PLC γ 1和PI3K的信号传导在 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：确定监管 EGFR和含α 6整合素对特异性信号传导的作用 控制SMG分支形态发生的组分。拟议的研究 将对理解正常发育机制具有重要意义， 定义导致先天性畸形或转化的功能障碍 导致癌症，并促进再生和组织 唾液腺工程

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.