Axonal Growth Cone Signal Transduction

描述(由申请人提供)：神经系统功能严重依赖于在发育过程中定义的连接模式，根据经验修改，并在疾病中受到干扰。在拟议的研究中，我们将重点关注轴突生长锥信号转导的三个具体方面。 第一个目标是提供对Sema3信号的全面理解。由于3类信号量作为生长锥体崩溃因子的核心作用，以及丛蛋白细胞质结构域的独特性质，这项工作将以一种中心的方式帮助理解轴突引导。通过在第二个目标中探索RGM/negenin信号，将确定最近定义的一类轴突指导因子的作用基础，以及negenin与DCC的信号特异性。从目标1和目标2得出的基本轴突引导机制的理解为正在进行的关于人类疾病状态下轴突误导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的知识基金。 在第三个目标中，考虑了一种可能与轴突引导改变有关的特定人类疾病。这些工作可能有助于理解轴突连通性的基因决定的改变如何导致人类疾病。虽然ADPEAF中的LGI1突变不是一种常见的癫痫形式，但很可能是平行通路导致了更多的散发性癫痫病例。总之，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。这些发现将对了解大脑发育障碍有意义，并将有助于设计基于轴突生长和再生的治疗方法。

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