DEVELOPMENT OF THE PALATE AND CRANIOFACIAL MESENCHYME

腭和颅面间充质的发育

• 批准号: 6176631
• 负责人: ELIZABETH D HAY
• 金额: $ 24.57万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6176631
• 关键词: antibody; cell cell interaction; cell transformation; chick embryo; cleft palate; connective tissue development; craniofacial; developmental genetics; electroporation; embryo /fetus tissue /cell culture; embryogenesis; epithelium; histogenesis; integrins; intercellular connection; laboratory mouse; mesenchyme; palate; transforming growth factors

DESCRIPTION (adapted from the Investigator's abstract): The broad objective of this application is to understand the tissue transitions involved in the development of the palate and craniofacial mesenchyme. Transformation of the medial edge epithelia (MEE) to mesenchyme in the paired palatal shelves from avian and rodent models will be examined. This represents a model for embryonic tissue remodeling and has potential importance to better understand failure of the palatal shelves to fuse in humans. The Principal Investigator's laboratory was the first to propose and demonstrate that the MEE undergoes epithelial-mesenchymal transformation (EMT) after fusing to form a midline seam, and that the resulting mesenchymal cells become part of the palate connective tissue, thus establishing confluence of the palatal stroma. It is likely that EMT is involved in other craniofacial processes where epithelial fuse, consequently studies are proposed to examine the formation of the upper lip. Understanding the cellular mechanism of palatal EMT will result in new approaches to defining the causes of congenital facial anomalies, such as cleft palate and other facial clefts that may result from failure of the EMT process. The specific aims are to study (1) the role of cell-cell contacts between opposing palatal shelves in initiation of EMT in the MEE; (2) the role of cell-matrix interactions and TGF-beta3 in the emigration phase of EMT; and (3) the role of defective EMT in cleft palate and in cleft lip. It is expected that beta-catenin and plakoglobin associated with the newly formed MEE junctions are the signaling molecules involved in initiating palatal EMT. Also it is expected that matrix-stimulated tyrosine kinases interact with growth factors at the plasmalemma level to promote emigration. Knowledge of the basic cell biology will lead to more effective treatment of human facial clefting.

描述（改编自研究者摘要）：本申请的主要目的是了解腭和颅面间充质发育中涉及的组织转变。将检查来自鸟类和啮齿动物模型的成对腭架中的内侧边缘上皮细胞（EEP）向间充质的转化。这代表了胚胎组织重塑的模型，并且对于更好地理解人类腭架融合失败具有潜在的重要性。主要研究者的实验室是第一个提出并证明腭突在融合形成中线缝后经历上皮-间充质转化（EMT），并且所产生的间充质细胞成为腭结缔组织的一部分，从而建立腭基质的汇合。EMT可能参与了其他颅面上皮融合的过程，因此建议研究上唇的形成。了解腭EMT的细胞机制将导致新的方法来定义先天性面部异常的原因，如腭裂和其他面部裂缝，可能导致EMT过程的失败。具体的目的是研究（1）在启动EMT在腭骨相对腭架之间的细胞-细胞接触的作用;（2）细胞-基质相互作用和TGF-β 3在EMT的迁移阶段的作用;和（3）有缺陷的EMT在腭裂和唇裂中的作用。预期与新形成的EMT连接相关的β-连环蛋白和斑珠蛋白是参与启动腭EMT的信号分子。还预期基质刺激的酪氨酸激酶在质膜水平与生长因子相互作用以促进迁移。基础细胞生物学的知识将导致更有效的治疗人类面部裂缝。