How Does a4B1 Integrin Regulate Cell Migration?

a4B1整合素如何调节细胞迁移？

• 批准号: 6576866
• 负责人: JOY YANG
• 金额: $ 29.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576866
• 关键词: angiogenesis; biological models; biological signal transduction; cell adhesion molecules; cell migration; cell proliferation; cell sorting; chimeric proteins; gene deletion mutation; gene targeting; genetically modified animals; genotype; histogenesis; integrins; laboratory mouse; ligands; macrophage; neurogenesis; peripheral nervous system; phenotype; protein structure function; receptor expression; terminal nick end labeling; transfection /expression vector

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.

描述(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底物之间的分子相互作用。这项建议侧重于细胞黏附受体Alpha4beta1在小鼠发育过程中细胞迁移中的作用。我们已经建立了一个小鼠模型，其中LacZ报告基因被敲入在alpha4整合素基因座上，用LacZ取代alpha4，并将LacZ置于alpha4启动子的控制下。对这只小鼠的分析表明，在心脏发育过程中，Alpha4beta1在心外膜祖细胞的迁移中扮演着重要的角色。在第一个目标中，我们将扩展我们对这一小鼠模型的分析，并确定alpha4beta1在发育过程中其他迁移事件中的新角色。我们还将通过有条件地或在特定组织中敲除α4来研究α4β1在发育后期的体内功能。其他人已经证明，在培养的细胞中，α4beta1以一种独特的方式促进细胞迁移。然而，关于alpha4beta1如何在体内调节细胞迁移，人们知之甚少。有人假设整合素可能通过由内而外和由外而内的信号事件来调节细胞迁移。在目标2中，我们将使用小鼠敲入策略来测试字母4的细微突变，这些突变扰乱了由内向外或由外向内的信号。我们将确定携带这些突变的alpha4 cDNA是否可以挽救由alpha4零突变引起的心外膜移行缺陷。这些研究将使我们能够阐明依赖于α4β1的迁移受到调控的机制。