CYTOSKELETAL REGULATION DURING GROWTH CONE GUIDANCE

生长锥引导期间的细胞骨架调节

• 批准号: 7498866
• 负责人: FRANK B GERTLER
• 金额: $ 9.52万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498866
• 关键词: Actins; Animals; Axon; Behavior; Binding; Biochemical; Biological Assay; Caenorhabditis elegans; Complex; Cues; Cytoskeletal Modeling; Cytoskeleton; Dominant-Negative Mutation; Electron Microscopy; Electrons; Embryonic Development; Family; Filopodia; Goals; Grant; Growth Cones; Guanosine Triphosphate Phosphohydrolases; Injury; Life; Ligands; Light; Link; Lipids; Localized; Locomotion; Mechanics; Mediating; Methods; Microfilaments; Microscopic; Movement; Nervous system structure; Neurons; Numbers; Output; PH Domain; Pathway interactions; Personal Satisfaction; Phosphorylation Site; Phosphotransferases; Pica Disease; Polymers; Positioning Attribute; Protein Family; Protein Kinase; Proteins; RNA Interference; Reagent; Regulation; Resolution; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Structure of posterior inferior cerebellar artery; Testing; Work; axon guidance; axonal guidance; cellular imaging; design; gene function; genetic manipulation; genetic regulatory protein; insight; link protein; migration; mutant; novel; phosphoinositide-3,4-bisphosphate; protein kinase A kinase; reconstitution; repaired; research study; response; second messenger; tool

During embryonic development, vast numbers of neurons must form connections with their proper targets. Axons are guided to their targets by growth cones, which integrate and convert guidance signals into mechanical forces required for locomotion. Movement arises from dynamic regulation of cytoskeletal polymers and associated proteins. The Ena/VASP protein family functions in various axon guidance pathways and is known to regulate the assembly of actin filaments. Ena/VASP proteins are concentrated in the tips of growth cone filopodia, where the initial response to guidance signals occurs. Several signaling pathways implicated in axon guidance regulate Ena/VASP function. Therefore, Ena/VASP proteins are well positioned to act as key convergence points between signals from guidance pathways and the actin cytoskeleton. We will test the hypothesis that Ena/VASP proteins regulate actin remodeling in response to guidance signals. We propose to examine the role of Ena/VASP in growth cone guidance and translocation using high-resolution light and electron microscopy to analyze cytoskeletal dynamics and geometry. We will also employ genetic manipulation to perturb Ena/VASP function and biochemical approaches to study Ena/VASP's role in signaling pathways. This work should yield valuable insight into how the nervous system develops and how to design methods to repair it after injury.

在胚胎发育过程中，大量的神经元必须与它们的固有神经元形成连接。 目标的轴突被生长锥引导到它们的目标，生长锥将引导信号整合并转换成 运动所需的机械力。运动源于细胞骨架的动态调节 聚合物和相关蛋白质。Ena/VASP蛋白家族在各种轴突导向中的功能 已知其调节肌动蛋白丝的组装。Ena/VASP蛋白集中在 生长锥丝状伪足的尖端，对引导信号的初始反应发生在那里。几种信号传导 参与轴突导向的通路调节Ena/VASP功能。因此，Ena/VASP蛋白很好地 定位为引导通路信号和肌动蛋白信号之间的关键汇聚点， 细胞骨架我们将检验Ena/VASP蛋白调节肌动蛋白重塑的假设， 引导信号。我们建议检查Ena/VASP在生长锥引导中的作用， 使用高分辨率光学和电子显微镜分析细胞骨架动力学， 几何我们还将采用遗传操作来干扰Ena/VASP功能和生物化学性质。 研究Ena/VASP在信号通路中的作用。这项工作应该产生有价值的见解， 神经系统如何发育以及如何设计损伤后的修复方法。