Vav GDP/GTP exchange factors in chemotaxis

Vav GDP/GTP 趋化性交换因子

• 批准号: 6702503
• 负责人: Joan Siefert Brugge
• 金额: $ 41.11万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-16 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702503
• 关键词: actins; cell adhesion molecules; cell line; cell migration; chemoattractants; chemotaxis; cytoskeleton; enzyme activity; gene mutation; genetically modified animals; guanine nucleotide binding protein; guanine nucleotide exchange factors; integrins; laboratory mouse; macrophage; neutrophil; protein structure function

DESCRIPTION (provided by the Applicant): Leukocyte chemotaxis plays a critical in the body's defense against microorganisms and hyperactivity of these cells leads to a variety of pathologic states including inflammation, vasculitis, and glomerulonephritis. Chemotaxis is dependent on the dynamic activity of adhesive and actin cytoskeletal structures that regulate cell motility. Rho GTPases are central players in the regulation of cell adhesion and actin cytoskeletal polymerization and assembly into cytoskeletal structures. We have found that Vav family Rho GTPase exchange factors are required for chemotaxis mediated by the chemoattractant fMLP and for macrophage migration on an extracellular matrix. This conclusion was based on studies of mice deficient in two Vav family members, Vav1 and Vav3. This proposal will examine the mechanisms involved in activation of Vav by chemoattractants and integrins and establish the mechanisms whereby this multidomain scaffolding protein regulates actin cytoskeletal structures and controls cell migration. The latter will involve defining regions of Vav that are required for motility and identification of effectors that mediate the activity of these domains. In addition we will analyze neutrophil and macrophage motility in mice lacking all three Vav family members since they are all expressed in these two cell types. These studies promise to elucidate pathways that are important in the host defense again microorganisms and pathologic inflammatory states.

描述（由申请人提供）： 白细胞趋化性在人体抵御微生物和细菌的过程中发挥着至关重要的作用 这些细胞的过度活跃会导致多种病理状态，包括炎症、 血管炎和肾小球肾炎。趋化性取决于 调节细胞运动的粘附和肌动蛋白细胞骨架结构。 Rho GTPases 是核心 细胞粘附和肌动蛋白细胞骨架聚合和组装调节的参与者 进入细胞骨架结构。我们发现 Vav 家族 Rho GTPase 交换因子是 趋化剂 fMLP 介导的趋化性和巨噬细胞所需的 细胞外基质上的迁移。这一结论是基于对缺乏 Vav 家族的两个成员，Vav1 和 Vav3。该提案将审查所涉及的机制 趋化剂和整合素激活 Vav 的过程，并建立其机制 这种多结构域支架蛋白调节肌动蛋白细胞骨架结构并控制细胞 迁移。后者将涉及定义运动性和所需的 Vav 区域。 识别介导这些域活动的效应器。此外我们还将 分析缺乏所有三个 Vav 家族成员的小鼠的中性粒细胞和巨噬细胞运动性 因为它们都在这两种细胞类型中表达。这些研究有望阐明 在宿主防御微生物和病理学中起重要作用的途径 炎症状态。