TGF-? SIGNALING DURING MOUSE SECONDARY PALATE ELEVATION AND FUSION

转化生长因子-？

• 批准号: 8167652
• 负责人: Jixiang Ding
• 金额: $ 17万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167652
• 关键词: Adhesions; Cleft Palate; Computer Retrieval of Information on Scientific Projects Database; Congenital Abnormality; Development; Down-Regulation; Funding; Gene Targeting; Genes; Genetic; Grant; Growth; Institution; Investigation; Mediating; Mus; Palate; Pathway interactions; Research; Research Personnel; Resources; Secondary Palate; Signal Pathway; Signal Transduction; Signaling Molecule; Source; Testing; Tissues; Tongue; United States National Institutes of Health; cell motility; malformation; mutant; notch protein; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cleft palate is a common birth defect caused by malformation in secondary palate development. Palate formation requires signaling pathways to function interactively rather than in isolation. However, our understanding of the signaling networks during palate fusion, growth and elevation remains poor. The proposed research will focus on the interactions among major signaling pathways during palate development. TGF-¿3 is an essential signaling molecule mediating palate fusion, but the mechanism of action is unknown. We found that TGF-¿3 is required for the down-regulation of Jag2 expression during fusion, suggesting TGF-¿ and Notch pathways function synergistically during fusion. Jag2, IRF6 and IKKa are key regulator factors in preventing pathogenic palate fusion with the tongue and other tissues, and recent studies have revealed the integration of these factors in controlling palate adhesion and fusion. We will pursue two specific aims: I) Interactions between TGF-¿3, Notch1/Jag2 during normal and pathogenic palate fusion. We will 1) take a genetic approach to test the hypothesis that TGF-¿3 mediates palate fusion by down-regulating Jag2 expression in the MEE; 2) investigate the functional significance of Jag2 down-regulation in MEE during wild type palate fusion. II) Investigation of TGF-¿ signaling and its interaction with Wnt5a during palate elevation. We will 1) investigate the downstream target genes of Zfhx1a during palate elevation focusing on the genes involving cell migration; 2) investigation of the function of TGF-¿1,2 during palate by generating TGF-¿1,2 double mutants; 3) examine the effects of TGF-¿s on Wnt5a mediated non-canonical signaling.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 腭裂是一种常见的出生缺陷，由腭二次发育畸形引起。上颚的形成需要信号通路相互作用而不是孤立地发挥作用。然而，我们对上颚融合、生长和抬高过程中的信号网络的理解仍然很差。拟议的研究将重点关注味觉发育过程中主要信号通路之间的相互作用。 TGF-¿3是介导腭融合的重要信号分子，但作用机制尚不清楚。我们发现融合过程中 TGF-¿3 是 Jag2 表达下调所必需的，这表明 TGF-¿ 和 Notch 通路在融合过程中协同发挥作用。 Jag2、IRF6和IKKa是防止致病性腭与舌头和其他组织融合的关键调节因子，最近的研究揭示了这些因子在控制腭粘连和融合中的整合。我们将追求两个具体目标： I) 正常和致病性腭融合过程中 TGF-¿3、Notch1/Jag2 之间的相互作用。我们将 1) 采用遗传学方法来检验 TGF-¿3 通过下调 MEE 中 Jag2 表达来介导上腭融合的假设； 2)研究野生型上颚融合过程中MEE中Jag2下调的功能意义。 II) 上腭抬高过程中 TGF-¿ 信号传导及其与 Wnt5a 相互作用的研究。我们将1）研究上腭抬高过程中Zfhx1a的下游靶基因，重点关注涉及细胞迁移的基因； 2) 通过产生TGF-¿1,2双突变体来研究TGF-Ф1,2在上腭过程中的功能； 3) 检查 TGF-¿ 对 Wnt5a 介导的非规范信号传导的影响。