Enhancement of Neuronal Plasticity and Axon Regeneration Capabilities of Pro-Neur

描述（由申请人提供）：人类作为温血脊椎动物，中枢神经系统（CNS）的轴突不能自发再生。相反，冷血脊椎动物的中枢神经系统显示出非凡的神经再生能力。对神经再生分子机制的研究已经发现了一些在成功的神经再生过程中诱导的蛋白质。对硬骨鱼视神经再生系统的分析使我们鉴定出RICH蛋白。我们的实验室在生化和细胞水平上对斑马鱼RICH （zRICH）蛋白的几种突变版本进行了研究。该蛋白是一种2',3'-环核苷酸，3'-磷酸二酯酶，可通过c端膜定位结构域与细胞膜结合。有趣的是，我们最近的研究表明，zRICH可以与微管蛋白结合，通过促进神经突分支的形成来增强神经元的可塑性。该蛋白的中心结构域足以与微管蛋白相互作用，但不足以诱导神经生成。这个项目的目的之一是了解更多关于……的影响的细节

DESCRIPTION (provided by applicant): Humans, as warm-blooded vertebrates, do not regenerate axons in their central nervous system (CNS) spontaneously. Conversely, cold-blooded vertebrates demonstrate remarkable abilities for nerve regeneration in their CNS. Studies of the molecular mechanisms of nerve regeneration have led to the discovery of several proteins that are induced during successful nerve regeneration. Analysis of the teleost fish optic nerve regeneration system led us to the identification of the RICH proteins. Several mutant versions of zebrafish RICH (zRICH) proteins have been generated and studied in our laboratory at the biochemical and cellular levels. This protein is a 2', 3'-cyclic nucleotide, 3'-phosphodiesterase that can bind to cellular membranes through a C-terminal membrane localization domain. Interestingly, our recent studies have shown that zRICH can bind to tubulin and enhance neuronal plasticity by promoting the formation of neurite branches. The central domain of the protein is sufficient for interaction with tubulin, but not for induction of neuritogenesis. One of the aims of this project is to learn additional details about the effects of zRICH in neuronal plasticity. Additional mutant versions of zRICH will be studied with our PC12 differentiation model, to learn whether the membrane localization domain or the acidic N-terminal domain play roles in neuritogenesis. A second aim is to explore the possibility of synergism of zRICH with other neuronal plasticity enhancing proteins such as GAP43 and CAP23. A third goal is exploring whether the plasticity enhancing effects can be applied to neural stem cells. The studies are relevant to public health by providing a better understanding of the process of nerve regeneration, and novel tools for the treatment of human diseases caused by damage to nerve fibers in the CNS, for example spinal cord injury.