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

描述(申请人提供)：人类，作为温血脊椎动物，不会自发地再生中枢神经系统(CNS)中的轴突。相反，冷血脊椎动物在其中枢神经系统表现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在成功的神经再生过程中诱导的几种蛋白质。通过对硬骨鱼视神经再生系统的分析，我们鉴定出了丰富的蛋白质。我们实验室已经产生了几种富含斑马鱼(ZRICH)蛋白的突变版本，并在生物化学和细胞水平上进行了研究。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，并通过促进轴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，但不能诱导神经发生。这个项目的目的之一是了解更多关于 富含神经元的可塑性。我们将使用我们的PC12分化模型来研究ZRICH的其他突变版本，以了解膜定位结构域或酸性N-末端结构域在神经发生中发挥的作用。第二个目的是探索ZRICH与其他神经可塑性增强蛋白如GAP43和CAP23协同作用的可能性。第三个目标是探索这种可塑性增强效应是否可以应用于神经干细胞。这些研究通过更好地了解神经再生的过程，以及治疗中枢神经系统神经纤维损伤引起的人类疾病(例如脊髓损伤)的新工具，与公共健康相关。

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.