THE ROLE OF TGF-BETA3 IN PALATOGENESIS

描述(由申请人提供)：这项建议的长期目标是了解在腭部融合过程中发生的转化生长因子-β信号的具体分子机制。这一点非常重要，因为这些过程的失败已被证明会导致腭裂，这是人类最常见的出生缺陷之一。其他人和我们之前已经证明，在腭裂融合过程中，转化生长因子-β(转化生长因子-β)诱导了几个下游反应，从而促进了成功的腭裂形成。这项建议侧重于上皮和间充质转化生长因子-β信号在协调腭裂融合中的作用。我们的总体假设是：转化生长因子-β/骨形态发生蛋白信号在腭部间充质和上皮细胞中都是成功融合的关键，并在腭部形成过程中发挥协同作用。我们建议通过五个具体目标来检验这一假设。在目标1中，我们建议确定神经脊细胞特异性地去除转化生长因子-b I型受体AIk2在腭部发育中的作用。在目标2中，我们建议确定转化生长因子-βI型受体AIk2和AIk5在腭部融合过程中的作用；在目标3中，我们建议确定相互的上皮-间充质转化生长因子-β信号在腭部融合中的作用；在目标4中，我们建议分析为什么腭上皮和间质之间的直接接触可以绕过转化生长因子-β3信号缺陷；在目标5中，我们建议确定缝隙连接在转化生长因子-β诱导的腭中线上皮融合中的作用。 我们独特的实验模型和最先进的策略使我们能够通过AIk5和AIk2确定转化生长因子-β信号在腭裂形成中的作用。总的来说，拟议的实验可能对于试图了解人类面部和腭裂的分子基础，以及开发可能的治疗方法来治疗胎儿时期的腭裂具有至关重要的意义。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand specific molecular mechanisms of Tgf-beta signaling that take place during palatal fusion. This is very important since failure of these processes has been shown to lead to cleft palate, one of the most common birth defects in humans. Others and we have previously shown that during palatal fusion transforming growth factor-betas (Tgf-betas) induce several downstream responses that contribute to the successful palatogenesis. This proposal focuses on the role of epithelial and mesenchymal Tgf-beta signals in coordination of palatal fusion. Our overall hypothesis is: Tgf-beta/Bmp signaling events both in the palatal mesenchyme and in the epithelium are critical for successful palatal fusion and play a concerted role during palatogenesis. We propose to test this hypothesis by five Specific Aims. In Aim 1 we propose to determine the effect of neural crest cell specific abrogation of the Tgf-b type I receptor AIk2 on palatal development. In Aim 2, we propose to define the role of Tgf-beta type I receptors AIk2 and AIk5 in the palatal midline epithelium during palatal fusion, in Aim 3 we propose to determine the role of reciprocal epithelio-mesenchymal Tgf-beta signaling during palatal fusion, in Aim 4 we propose to analyze why direct contact between the palatal epithelium and mesenchyme can bypass the Tgf-beta3 signaling defect, and finally in Aim 5 we propose to determine the role of gap junctions in Tgf-beta-induced palatal midline epithelial fusion. Our unique experimental models and the state-of-art strategy allow us to determine the role Tgf-beta signaling via AIk5 and AIk2 in palatogenesis. Collectively, the proposed experiments are likely to be of critical importance in attempting to understand the molecular bases of facial and palatal cleftings in humans, and to develop possible therapeutic approaches to treat cleft palate during the fetal period.