Axonal Growth Cone Signal Transduction

轴突生长锥信号转导

• 批准号: 7233136
• 负责人: STEPHEN M STRITTMATTER
• 金额: $ 35.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-17 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7233136
• 关键词: Affinity; Autosomal Dominant Partial Epilepsy with Auditory Features; Axon; Binding; Brain; Cell Differentiation process; Cell Survival; Cells; Class; Clinical; Complex; Condition; Cytoplasmic Tail; Dependence; Development; Disease; Endocytosis; Ephrins; Epilepsy; Funding; Genes; Growth; Growth Cones; Human; Induced Mutation; Inherited; Intervention; Ions; Knowledge; LGI1 gene; Laboratories; Lead; Learning; Ligands; Link; Mediator of activation protein; Microtubules; Molecular; Monitor; Mus; Mutation; Natural regeneration; Nature; Nervous System Physiology; Nervous system structure; Neurites; Neuropilins; Numbers; PTK2 gene; Pathway interactions; Pattern; Phenotype; Physiological; Play; Protein Tyrosine Kinase; Proteins; RanBMP-90; Regulation; Relative (related person); Role; Semaphorins; Sequence Homology; Signal Transduction; Specificity; System; Testing; Treatment Protocols; Work; axon growth; axon guidance; axon regeneration; axonal guidance; base; developmental disease; experience; human disease; in vivo; insight; intersectin 1; mutant; neogenin; nerve stem cell; netrin receptor; neurite growth; novel; plexin; protein distribution; receptor; therapy design

DESCRIPTION (provided by applicant): Nervous system function is critically dependent on the pattern of connectivity that is defined during development, modified by experience and perturbed in disease. We will focus on three specific aspects of axon growth cone signal transduction in the proposed studies. The first aim is to provide a comprehensive understanding of Sema3 signaling. Because of the central role of class 3 Semaphores as growth-cone-collapsing agents and of the unique nature of the Plexin cytoplasmic domain, this work will contribute in a central way to understanding axon guidance. By exploring RGM/Neogenin signaling in the second aim, the basis of action for a recently defined class of axon guidance factor and the signaling specificity of Neogenin versus DCC will be defined. The understanding of basic axon guidance mechanisms derived from Aims 1 and 2 lays the groundwork for ongoing studies of axonal misdirection and failed growth in human disease states. Any attempts at clinical intervention must draw on such a fund of knowledge. In the third aim, a specific human disease that may be linked to altered axon guidance is considered. Such work may provide an understanding of how genetically determined alterations in axonal connectivity can lead to human disease. While LGI1 mutation in ADPEAF is not a common form of epilepsy, it is likely that parallel pathways are causative in a larger number of sporadic cases of epilepsy. Together these studies will provide novel molecular insights into how nervous system connectivity is assembled or misassembled during development. These findings will have implications for the understanding developmental disorders of the brain arid will aid in the design of therapies based on axonal growth and regeneration

描述（由申请人提供）：神经系统功能严重依赖于发育期间定义的连接模式，通过经验进行修改并在疾病中受到干扰。我们将集中在轴突生长锥信号转导的三个具体方面的建议的研究。 第一个目的是提供对Sema 3信号传导的全面理解。由于3类信号作为生长锥崩溃剂和丛状蛋白胞质结构域的独特性质的中心作用，这项工作将有助于在一个中心的方式来理解轴突的指导。通过在第二个目标中探索RGM/再生蛋白信号传导，将定义最近定义的一类轴突引导因子的作用基础和再生蛋白相对于DCC的信号传导特异性。对源自目标1和2的基本轴突引导机制的理解为正在进行的人类疾病状态下轴突错误方向和失败生长的研究奠定了基础。任何临床干预的尝试都必须利用这样一个知识库。 在第三个目标中，考虑了可能与改变的轴突引导有关的特定人类疾病。这项工作可能会提供一个理解如何遗传决定轴突连接的改变可以导致人类疾病。虽然ADPEAF中的LGI 1突变不是癫痫的常见形式，但在大量散发性癫痫病例中，平行途径可能是病因。 这些研究将为神经系统连接在发育过程中如何组装或错误组装提供新的分子见解。这些发现将有助于理解大脑发育障碍，并有助于设计基于轴突生长和再生的治疗方法。