Rac2 in reglation of cytoskeletal function

Rac2 调节细胞骨架功能

• 批准号: 6595711
• 负责人: Simon J. Atkinson
• 金额: $ 21.74万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-22 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6595711
• 关键词: actins; biological signal transduction; cell component structure /function; cytoskeleton; dendritic cells; gene targeting; genetically modified animals; guanine nucleotide binding protein; guanosinetriphosphatases; hematopoietic stem cells; laboratory mouse; macrophage; microfilaments; neutrophil

Rho GTPases are widely recognized as the critical integrators of signals from the cell surface that control cell morphology and motility in all eukaryotic cell types examined, including hematopoietic cells. The ultimate targets of these signals are alterations in the organization of the actin cytoskeleton. Signals from Rac, a rho family GTPase, result in actin polymerization at the cell periphery that is crucial for extension of the leading edge of crawling cells, for the phagocytosis of pathogens and for correct uptake and presentation of antigen by dendritic cells. The generation of a strain of mice deficient in the hematopoietic-specific GTPase Rac2 provides a unique animal model in which to study the role of signaling pathways utilizing this GTPase in their physiological context. Mice deficient in Rac2 exhibited multiple defects in neutrophil functions related to the actin cytoskeleton including chemotaxis, integrin- and selectin-mediated adhesion and phagocytosis. Underlying these defects appears to be a disturbance in actin dynamics at rest and in response to stimulus. We propose studies to determine the mechanisms by which Rac2 deficiency results in disturbed actin dynamics. We will characterize the phenotypes of Rac2 deficient macrophages, neutrophils and dendritic cells that relate to actin dynamics, and using retroviral transduction we will determine the requirement for Rac2-specific sequences for normal function in these cell types. The will determine the requirement for Rac2-specific sequences for normal function in these cell types. We will determine the mechanistic basis for disturbed actin dynamics in the absence of Rac2 by measuring the roles of de novo nucleation of actin filaments and barbed end uncapping, and the roles of components of signaling pathways that lie between Rac and components of the actin cytoskeleton. Studies described in this project will further understanding of the role of the cytoskeleton and the pathways that control it in innate and acquired immunity.

Rho GTPases被广泛认为是来自细胞表面的信号的关键积分器，该信号的控制细胞形态和运动能力在所有检查的真核细胞类型中，包括造血细胞。这些信号的最终目标是肌动蛋白细胞骨架组织的改变。 RAC的RAC（一种RHO家族GTPase）的信号在细胞周围导致肌动蛋白聚合，这对于延伸爬行细胞的前缘至关重要，对于病原体的吞噬作用以及树枝状细胞对抗原的正确摄取和表现。缺乏造血特异性GTPase Rac2的小鼠菌株的产生提供了一种独特的动物模型，在该模型中，在其生理环境中利用该GTPase利用该GTPase的信号传导途径的作用。缺乏RAC2的小鼠在与肌动蛋白细胞骨架有关的中性粒细胞功能中表现出多种缺陷，包括趋化性，整联蛋白和选择素介导的粘附和吞噬作用。这些缺陷的基础似乎是静止和响应刺激的肌动蛋白动力学的干扰。我们提出的研究以确定RAC2缺乏导致肌动蛋白动力学的机制。我们将表征与肌动蛋白动力学相关的Rac2缺乏巨噬细胞，中性粒细胞和树突状细胞的表型，并使用逆转录病毒转导我们将确定对这些细胞类型中正常功能的RAC2特异性序列的要求。将确定这些细胞类型中正常功能的RAC2特异性序列的要求。我们将通过测量肌动蛋白细丝和带状末端解蛋白的从头核的作用，以及在RAC2的NOK NOCLEATION的作用以及RAC与肌动蛋白细胞骨架的RAC组成部分和肌动蛋白之间的成分之间的作用来确定肌动蛋白动力学的机械基础。该项目中描述的研究将进一步了解细胞骨架的作用以及控制其先天和获得免疫力的途径。