Regulation of cell transformation

在心脏发育过程中，心瓣膜祖细胞在tgf β介导的心肌和内皮之间的相互作用下从心脏内皮细胞发育而来。内皮细胞的这种“上皮-间充质细胞转化”被认为是由于“主基因”的调控，是ECM或其受体变化的结果，或者是内皮细胞失去细胞间粘附的结果。虽然这些假设的各个方面都可能涉及到内皮细胞的粘附。虽然这些假设的各个方面都可能涉及，但本实验室获得的数据表明，在细胞转化过程中发生了复杂的调节过程。我们的假设是上皮间质细胞转化是多种转录因子通过不同的信号转导途径协调调节的结果。为了探索这一假设，我们将重点关注两个关键事件的调节。第一种是以细胞形态变化为特征的激活过程第二种是以细胞形态变化为特征的激活过程第二种是细胞侵入底层ECM的过程。这些事件似乎与两个特定的转录因子Slug和Mox-1有关。Slug在细胞激活过程的早期起作用，而Mox-1在细胞侵袭过程中起作用。在心脏中发现的第三个转录因子Snail将被研究，因为它可能与Slug有冗余活性。我们以前表明，几种不同的转导途径介导内皮细胞对转化刺激的反应。下一阶段的工作是将信号转导与特定的基因调控联系起来。我们将使用多种试剂来确定Mox-1和Slug是通过感应刺激并联还是串联调节的。具体目标是：1.；通过各种信号通路扩展内皮细胞和间充质细胞中Mox-1和Slug调节的特征。2. 鉴定Mox1和Slug上游序列中介导特定信号转导通路反应的启动子/增强子元件。3. 检测Smads在细胞转化时通过TGFbeta参与Slug或Mox1的调控。总之，这些目标将进一步表征心脏细胞发育的基本过程。

During cardiac development, valvular progenitors develop from cardiac endothelium in response to a TGFbeta-mediated tissue interaction between the myocardium and the endothelium. This "epithelial- mesenchymal cell transformation" of endothelial cells has been alternatively postulated to be due to the regulation of a "master gene", the result of changes in ECM or its receptors, or the loss of cell-cell adhesion by endothelial cells. While aspects of each of these hypotheses are likely to be involved, adhesion by endothelial cells. While aspects of each of these hypotheses are likely to be involved, data obtained in this laboratory suggest that a complex regulatory process takes place during cell transformation. It is our hypothesis that epithelial-mesenchymal cell transformation is the result of coordinate regulation of several transcription factors by different signal transduction pathways. To explore this hypothesize we will focus on the regulation of two critical events. The first is an activation process characterized by a change in cell morphology and the second is a process is an activation process characterized by a change in cell morphology and the second is a process wherein cells invade the underlying ECM. These events appear to correlate with two specific transcription factors, Slug and Mox-1. Slug functions early in the cell activation process while Mox-1 functions during cellular invasion. A third transcription factor found in the heart, Snail, will be investigated as it may have a redundant activity with Slug. We previously showed that several distinct transduction pathways mediate endothelial responses to the transforming stimulus. The next phase of the work is to link signal transduction with specific gene regulation. We will use a variety of reagents to determine whether Mox-1 and Slug are regulated in parallel or in serial by the inductive stimulus. Specific aims are: 1. Extend characterizing of Mox-1 and Slug regulation in endothelial and mesenchymal cells by various signal pathways. 2. Identify promoter/enhancer elements in Mox1 and Slug upstream sequences that mediate responses to specific signal transduction pathways. 3. Test involvement of Smads in the regulation of Slug, or Mox1 via a TGFbeta the time of cell transformation. Together, these aims will further the characterization of the fundamental process of cell development in the heart.