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（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着核心作用。一个关键步骤是阐明细胞与细胞迁移的基质之间的分子相互作用。该建议的重点是细胞粘附受体α4Beta1在小鼠发育过程中细胞迁移中的作用。我们已经生成了一个小鼠模型，其中将LACZ报告基因在alpha4整合蛋白基因座上敲入，用LACZ代替Alpha4，并将LACZ放在Alpha4启动子的控制下。对该小鼠的分析揭示了α4Beta1在心脏发育过程中心外膜祖细胞迁移中的重要作用。在第一个目标中，我们将扩展对该鼠标模型的分析，并确定在开发过程中其他迁移事件中alpha4beta1的新作用。我们还将通过有条件地或特定组织中敲除α4的后期来研究α4Beta1的体内功能。其他人已经表明，在培养的细胞中，α4Beta1以独特的方式促进细胞迁移。然而，关于α4Beta1如何调节体内细胞迁移的知名度鲜为人知。已经假设整联蛋白可以通过内而外和外部信号事件调节细胞迁移。在AIM 2中，我们将使用鼠标敲入策略来测试alpha4中内外或外部信号传导中断的微妙突变。我们将确定携带这些突变的α4cDNA是否可以挽救由α4-null突变引起的心外膜迁移缺陷。这些研究将使我们能够阐明调节α4Beta1依赖性迁移的机制。