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 GTP酶被广泛认为是来自细胞表面的信号的关键整合子，其控制所检查的所有真核细胞类型（包括造血细胞）中的细胞形态和运动性。这些信号的最终目标是改变肌动蛋白细胞骨架的组织。来自Rac（rho家族GTPase）的信号导致细胞外周肌动蛋白聚合，这对于爬行细胞前沿的延伸、病原体的吞噬以及树突状细胞对抗原的正确摄取和呈递至关重要。产生的一个品系的小鼠缺乏的造血特异性GTcR ac 2提供了一个独特的动物模型，在其中研究的作用，信号通路利用这种GTcR在其生理环境。Rac2缺陷的小鼠表现出与肌动蛋白细胞骨架相关的中性粒细胞功能的多重缺陷，包括趋化性、整合素和选择素介导的粘附和吞噬作用。潜在的这些缺陷似乎是一个干扰肌动蛋白动力学在休息和对刺激的反应。我们提出的研究，以确定Rac2缺陷导致肌动蛋白动力学紊乱的机制。我们将表征与肌动蛋白动力学相关的Rac 2缺陷型巨噬细胞、中性粒细胞和树突状细胞的表型，并使用逆转录病毒转导，我们将确定这些细胞类型中正常功能对Rac 2特异性序列的需求。这将确定在这些细胞类型中正常功能对Rac2特异性序列的需求。我们将确定在没有Rac 2的情况下，通过测量肌动蛋白丝的从头成核和倒刺末端脱帽的作用，以及位于Rac和肌动蛋白细胞骨架组件之间的信号通路组件的作用，来确定肌动蛋白动力学紊乱的机制基础。本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在先天性和获得性免疫中的途径。