Regulation of cell transformation

细胞转化的调控

基本信息

批准号：
6493622
负责人：
RAYMOND Bruce RUNYAN
金额：
$ 28.8万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2002-07-31
项目状态：
已结题

项目摘要

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.

在心脏发育过程中，瓣膜祖细胞响应 TGFβ 介导的心肌与内皮之间的组织相互作用而从心脏内皮发育而来。内皮细胞的这种“上皮-间充质细胞转化”也被假设是由于“主基因”的调节、ECM或其受体变化的结果，或者是内皮细胞丧失细胞间粘附的结果。虽然这些假设的各个方面都可能涉及内皮细胞的粘附。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，细胞转化过程中发生了复杂的调节过程。我们假设上皮间质细胞转化是多种转录因子通过不同信号转导途径协调调节的结果。为了探索这个假设，我们将重点关注两个关键事件的调节。第一个过程是以细胞形态变化为特征的激活过程，第二个过程是以细胞形态变化为特征的激活过程，第二个过程是细胞侵入底层ECM的过程。这些事件似乎与两种特定的转录因子 Slug 和 Mox-1 相关。 Slug 在细胞激活过程的早期发挥作用，而 Mox-1 在细胞侵袭过程中发挥作用。将研究在心脏中发现的第三个转录因子 Snail，因为它可能与 Slug 具有冗余活性。我们之前表明，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 是否受到感应刺激的并行或串行调节。具体目标是： 1. 通过各种信号途径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 上游序列中介导对特定信号转导途径的反应的启动子/增强子元件。 3. 测试 Smads 通过 TGFbeta 对 Slug 或 Mox1 对细胞转化时间的调节的参与。这些目标共同将进一步表征心脏细胞发育的基本过程。