Spatial Regulation of Cytoskeleton During Chemotaxis

趋化过程中细胞骨架的空间调节

• 批准号: 8063042
• 负责人: CHANG Y CHUNG
• 金额: $ 30.54万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063042
• 关键词: Actins; Affect; Applications Grants; Arthritis; Binding; Biochemical; Biological Assay; Biological Process; Cell Polarity; Cells; Chemicals; Chemotactic Factors; Chemotaxis; Complex; Coupled; Cues; Cytoskeleton; Data; Defect; Dictyostelium; Disease; Endocytic Vesicle; Eukaryotic Cell; F-Actin; Goals; Golgi Apparatus; Heterotrimeric GTP-Binding Proteins; Kinesin; Life; Ligands; Malignant Neoplasms; Membrane; Microtubules; Molecular; Movement; Multiple Sclerosis; Mutation; Myosin ATPase; Nocodazole; Null Lymphocytes; Play; Positioning Attribute; Process; Protein Family; Proteins; Proteomics; Regulation; Research; Role; Secretory Vesicles; Signal Transduction Pathway; Sorting - Cell Movement; Stream; Testing; Vesicle; Wound Healing; axonal guidance; cell cortex; cell motility; cellular imaging; directional cell; insight; mutant; nervous system development; public health relevance; receptor binding; research study; response; trafficking

DESCRIPTION (provided by applicant): Many eukaryotic cells undergo chemotaxis, directed movement towards a soluble ligand. This process is necessary for many biological functions, including wound healing, axonal guidance, and the aggregation of Dictyostelium cells. Chemotaxis also plays a role in disease states such as arthritis, cancer, and multiple sclerosis. Directional cell movement requires a defined cell polarity in which components of the cytoskeleton are differentially localized at the leading edge of a migrating cell as well as its retracting posterior. This polarization can be initiated by the chemoattractant binding of heterotrimeric G protein-coupled membrane- bound receptors, and subsequent activation of downstream signal transduction pathways direct reorganization of the actin and myosin cytoskeleton. Our previous studies suggested that a polarized actin cytoskeleton is achieved by concentrating regulators of actin assembly such as WASP and WIP in subdomains at the cell cortex. The goal of this study is to understand how the subcellular localization and activation of WASP is regulated during chemotaxis. We hypothesize that a complex interplay between PCH family proteins, CLP1/2, and RacC leads to polarized trafficking of WASP and ACA, resulting in cell polarity establishment via the polarized organization of actin cytoskeleton and asymmetric distribution of ACA during Dictyostelium chemotaxis. To test this hypothesis, we propose the following specific aims: 1) To elucidate the role of PCH family proteins, CLP1/2 and RacC in controlling function and localization of WASP during vesicle formation. 2) To investigate roles of CLP1/2, RacC, and Unc104 in the trafficking of WASP- and ACA-vesicles. 3) To study how polarized trafficking of WASP- and ACA-vesicles contribute to establish cell polarity during chemotaxis. It is anticipated that these studies will serve not only to provide new insights on how exocytic vesicle formation from Golgi is controlled, but also to understand how cellular polarity can be achieved b vesicle trafficking during chemotaxis. PUBLIC HEALTH RELEVANCE: Many cells in our body undergo chemotaxis, directed movement toward a chemical compound which is necessary for many biological functions including wound healing and the development of the nervous system. Chemotaxis also plays a role in disease states such as arthritis, cancer, and multiple sclerosis. Our proposed research would help us understand how cells maintain cell polarity and directed cell movement when they migrate directionally toward a directional cue.

描述（由申请人提供）：许多真核细胞发生趋化性，直接向可溶性配体运动。此过程对于许多生物学功能，包括伤口愈合，轴突引导和柱状细胞的聚集是必需的。趋化性在关节炎，癌症和多发性硬化症等疾病状态中也起着作用。定向细胞运动需要定义的细胞极性，其中细胞骨架的成分在迁移细胞的前缘及其后骨后部差异化。这种极化可以通过异三聚体G蛋白偶联的膜结合受体的趋化剂结合，以及随后激活下游信号转导途径直接重新组织肌动蛋白和肌球蛋白细胞骨架。我们先前的研究表明，通过将肌动蛋白组装的调节剂（例如WASP和WIP）在细胞皮质的子域中浓缩来实现偏振肌动蛋白细胞骨架。这项研究的目的是了解在趋化性期间如何调节黄蜂的亚细胞定位和激活。我们假设PCH家族蛋白，CLP1/2和RACC之间的复杂相互作用导致WASP和ACA的极化运输，从而通过肌动蛋白细胞骨架的极化组织和ACA的非对称分布在Dictotoctelium tixoctelium pytoctelium pycotaxis过程中导致细胞极性建立。为了检验这一假设，我们提出了以下特定目的：1）阐明PCH家族蛋白，CLP1/2和RACC在囊泡形成过程中WASP的功能和定位中的作用。 2）研究CLP1/2，RACC和UNC104在黄蜂和ACA梭子的运输中的作用。 3）研究黄蜂和ACA-vesicle的极化运输如何有助于在趋化过程中建立细胞极性。可以预料，这些研究不仅将提供有关如何控制高尔基体外囊囊泡形成的新见解，而且还可以理解在趋化过程中如何实现细胞极性。 公共卫生相关性：我们体内的许多细胞都经历了趋化性，直接向化合物运动，这对于许多生物学功能（包括伤口愈合和神经系统的发展）所必需。趋化性在关节炎，癌症和多发性硬化症等疾病状态中也起着作用。我们提出的研究将帮助我们了解细胞在方向向方向提示方向迁移时如何保持细胞极性和定向细胞运动。