Vav GDP/GTP exchange factors in chemotaxis

描述(由申请人提供)： 白细胞趋化性在人体抵御微生物和 这些细胞的过度活跃会导致多种病理状态，包括炎症， 脉管炎和肾小球肾炎。趋化性依赖于其动态活性。 调节细胞运动的粘附性和肌动蛋白细胞骨架结构。Rho GTP酶是核心 细胞黏附和肌动蛋白细胞骨架聚合与组装的调控 变成了细胞骨架结构。我们发现Vav家族的Rho GTP酶交换因子是 趋化因子fMLP介导的趋化和巨噬细胞所需 在细胞外基质上迁移。这一结论是基于对缺乏营养物质的小鼠的研究 Vav家族的两个成员，Vav1和Vav3。这项提案将审查所涉及的机制 在趋化物质和整合素激活Vav中的作用 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。后者将包括定义运动和运动所需的Vav区域 识别调节这些区域活动的效应器。此外，我们还将 分析三种Vav家族成员缺失小鼠的中性粒细胞和巨噬细胞运动能力 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中起重要作用的途径 炎症状态。

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.