REGULATION OF ATRIOVENTRICULAR CANAL MESENCHYME FORMATION

胚胎心脏房室管的发育 其特征在于内皮-间充质细胞转化， 内皮细胞亚群。这些细胞改变表型， 侵袭性间充质细胞，是瓣膜的最早祖细胞， 心脏的隔膜结构通过使用胶原蛋白凝胶培养， 鸡胚胎材料，我们和其他人表明， 过程是由来自心肌的信号刺激的， 地域和时间上的特异性。初步研究发现， 生长因子TGF β作为转化过程的一个组成部分。 在上一个资助期，我们发现TGF β 3， TGF β家族，在心脏内有适当的分布。 此外，通过用以下物质处理心脏外植体来降低TGF β 3 mRNA水平： 修饰的反义寡核苷酸证实了这一直接作用。 在鸟类心脏中的分子。我们还发现了一种mRNA， 与心脏内的TGF β 3编码转录物杂交。这 反义RNA的分布和外观与在 调节TGF β 3信息翻译。进行了额外的研究 开始解决细胞转化的过程， 靶内皮组织中的信号传导和基因表达。 本文提出继续研究，以探索细胞转化在 心脏和调节TGF β 3在这个过程中。的具体目标 建议是：l）分析TGF β 3信息和蛋白质产生 在缓冲组织形成期间。2)表征反义TGF β 3 mRNA 如果合适的话，还包括它的蛋白质产物。3)表征 激活信号，调节反义TGF β 3转录。四、 检查信号转导分子和其他 在该SCOR中鉴定的分子，其可以直接与 胚胎心脏瓣膜形成或相关的形态发生过程。 这些研究将明确TGF β 3的作用及其在肿瘤发生中的调节作用。 心脏瓣膜和间隔间质的鉴别。的目标 这项工作是为了了解参与这一过程的分子信号， 诱导的表型变化。对这些过程的理解将 提供基本的发育原则和确定候选基因 和先天性心脏病的相互作用。

Development in the atrioventricular canal of the embryonic heart is characterized by an endothelial-mesenchymal cell transformation of a subpopulation of endothelial cells. These cells change phenotype to become invasive mesenchymal cells and are the earliest progenitors of valve and septal structures in the heart. Through use of collagen gel cultures of embryonic chicken material, we and others showed that the transformation process is stimulated by a signal from the myocardium and is both regionally and temporally specific. Preliminary studies had identified a growth factor, TGFbeta, as a component of the transformation process. During the previous grant period we showed TGFbeta3, among the members of the TGFbeta family, to have an appropriate distribution within the heart. Further, reduction of TGFbeta3 mRNA levels by treating heart explants with modified antisense oligonucleotides confirmed a direct role for this molecule in the avian heart. We have also identified an mRNA that may hybridize to TGFbeta3 encoding transcripts within the heart. This antisense RNA has a distribution and appearance consistent with a role in regulating TGFbeta3 message translation. Additional studies were performed to begin to address the process of cell transformation by identifying signal transduction and gene expression in the target endothelial tissue. Continuing studies are proposed here to explore cell transformation in the heart and the regulation of TGFbeta3 in this process. The specific aims of the proposal are to: l) Analyze TGFbeta3 message and protein production during cushion tissue formation. 2) Characterize antisense TGFbeta3 mRNA in the heart and, if appropriate, its protein product. 3) Characterize the activation signals which regulate antisense TGFbeta3 transcription. 4) Examine expression of signal transduction molecules and additional molecules identified within this SCOR which can be directly related to valve formation or related morphogenetic processes in the embryonic heart. These studies will define the role of TGFbeta3 and its regulation in the differentiation of cardiac valvular and septal mesenchyme. The goal of this work is to understand the molecular signals involved in this process of induced phenotypic change. An understanding of these processes will provide both basic developmental principles and identify candidate genes and interactions involved in congenital heart disease.