COMMITMENT & DIFFERENTIATION OF CARDIAC CELL PHENOTYPES

提出了一个由5个项目和2个核心组成的Program Project。主题是胚胎心脏内皮细胞和心肌细胞两种细胞类型的承诺和分化的探索之一。这一探索将结合五个项目共同的实验胚胎学和分子生物学进行。我们感兴趣的一个事件是房室管内皮细胞的上皮-间充质细胞转化，它产生了瓣膜和膜间隔的最早祖细胞。对这些细胞的研究将从三个层面探索细胞转化的调控。项目1将从三个层面探索转录因子Slug和Mox-1作为细胞转化的介质。项目1将探索转录因子Slug和Mox-1as在细胞转化过程中响应TGFbeta等信号转导途径的介质。项目2将探讨cadherins和β -catenin在细胞转化过程中下调细胞粘附的作用。项目3的重点是透明质酸合成酶2 （Has2）在心脏垫形成中的作用，以及透明质酸对细胞转化和迁移的明显需求。这组研究人员感兴趣的还有心肌细胞的发育。项目4是对Nkx （thinman）基因在心肌细胞前体对心脏表型的承诺中的作用的检查。项目5通过检查肌节的形成重点关注心肌细胞的分化。为了了解收缩装置的装配规律，提出了对第3和第4灯丝系统的探索。这五个项目得到行政和研究核心的支持。研究核心将提供反义寡核苷酸、病毒载体和全载原位杂交的共同能力。行政核心将向所有项目提供支助，并利用外部审查委员会和定期安排的顾问提供审查和反馈。该计划旨在加强成员实验室之间的沟通，促进心脏发育的协同探索。本项目所获得的信息将有助于我们对先天性心脏病的了解。

A Program Project consisting of 5 projects and 2 cores is proposed. The theme is one of an exploration of commitment and differentiation by two cell types in the embryonic heart, endothelia and myocytes. This exploration will be carried out by a combination of experimental embryology and molecular biology common to the five projects. One event of interest in the epithelial-mesenchymal cell transformation of endothelial cells in the atrioventricular canal that produces the earliest progenitors of the vales and membranous septa. Studies focused on these cells will explore the regulation of cell transformation at three levels. Project 1 will explore the transcription factors Slug and Mox-1 as mediators of cell transformation at three levels. Project 1 will explore the transcription factors Slug and Mox-1as mediators of cell transformation in response to TGFbeta and other signal transduction pathways. Project 2 will explore the role of cadherins and beta-catenin in the down-regulation of cell, cell adhesion that accompanies cell transformation. Project 3 is focused on the role of Hyaluronan Synthase 2 (Has2) in the formation of the cardiac cushions and the apparent requirement for hyaluronan for cell transformation and migration. Also of interest to this group of investigators is the development of cardiac myocytes. Project 4 is an examination of the role of Nkx (thinman) genes in commitment to the cardiac phenotype by myocyte precursors. Project 5 focuses on the differentiation of cardiac myocytes by examining the formation of the sarcomere. Exploration of the 3rd and 4th filament systems is proposed in order to understand the regulation of the assembly of the contractile apparatus. The five projects are supported by administrative and research cores. The research core will provide common capabilities in antisense oligonucleotides, viral vectors and whole mount in situ hybridization. The administrative core will provide support to all projects and utilize both an external review committee and regularly scheduled consultants to provide review and feedback. This program is designed to enhance communication between the member laboratories and promote the synergistic exploration of heart development. Information obtained by this Program Project will contribute significantly to our understanding of congenital heart disease.