How Does a4B1 Integrin Regulate Cell Migration?

描述（由申请人提供）：细胞迁移在胚胎发育、伤口愈合、炎症和肿瘤转移中起核心作用。关键的一步是阐明细胞和细胞迁移基质之间的分子相互作用。这项建议的重点是细胞粘附受体，α 4 β 1，在小鼠发育过程中的细胞迁移的作用。我们已经产生了一个小鼠模型，其中lacZ报告基因敲入α 4整联蛋白基因座，用lacZ取代α 4，并将lacZ置于α 4启动子的控制下。对这只小鼠的分析揭示了α 4 β 1在心脏发育期间心外膜祖细胞迁移中的重要作用。在第一个目标中，我们将扩展我们对这种小鼠模型的分析，并确定α 4 β 1在发育过程中其他迁移事件中的新作用。我们还将通过有条件地或在特定组织中敲除α 4来研究α 4 β 1在发育后期的体内功能。其他人已经表明，在培养的细胞中，α 4 β 1以独特的方式促进细胞迁移。然而，很少有人知道如何在体内α 4 β 1调节细胞迁移。据推测，整合素可能通过由内向外和由外向内的信号传导事件调节细胞迁移。在目标2中，我们将使用小鼠敲入策略来测试alpha4中的微小突变，这些突变会破坏由内而外或由外而外的信号传导。我们将确定携带这些突变的α 4 cDNA是否可以挽救由α 4无效突变引起的心外膜迁移缺陷。这些研究将使我们能够阐明α 4 β 1依赖性迁移的调节机制。

DESCRIPTION (provided by applicant): Cell migration plays a central role in embryonic development, wound healing, inflammation and tumor metastasis. A key step is to elucidate the molecular interactions between cells and the substrata on which cells migrate. This proposal focuses on the role of a cell adhesion receptor, alpha4beta1, in cell migration during mouse development. We have generated a mouse model in which the lacZ reporter gene is knocked-in at the alpha4 integrin locus, replacing alpha4 with lacZ and placing lacZ under the control of the alpha4 promoter. Analysis of this mouse has revealed an essential role of alpha4beta1 in the migration of epicardial progenitor cells during cardiac development. In the first aim, we will extend our analysis on this mouse model and identify new roles for alpha4beta1 in other migratory events during development. We will also study the in vivo functions of alpha4beta1 in later stages of development by knocking-out alpha4 conditionally or in specific tissues. It has been shown by others that in cultured cells alpha4beta1 promotes cell migration in a unique way. However, little is known as to how alpha4beta1 regulates cell migration in vivo. It has been hypothesized that integrins may regulate cell migration through inside-out and outside-in signaling events. In Aim 2, we will use a mouse knock-in strategy to test subtle mutations in alpha4 that disrupt inside-out or outside-in signaling. We will determine if alpha4 cDNAs carrying these mutations can rescue the epicardial migration defect caused by the alpha4-null mutation. These studies will allow us to elucidate mechanisms by which alpha4beta1-dependent migration is regulated.