神经轴突变性是急性神经损伤和多种慢性神经退行性疾病中的常见病变。轴突变性是一个积极主动、被高度调控的过程，譬如在动物体内高表达烟酰胺单核苷酸腺苷转移酶(Nmnat)可以显著推迟受损神经轴突的变性坏死。不仅如此，申请人在最近的工作中发现，降低生物体内Nmnat水平可以引发神经轴突自发性的变性坏死。由此可见，内源性的Nmnat基因对于维持神经轴突完整性起着不可或缺的重要作用，但其神经保护的分子机理尚不清楚。在本课题组的前期工作中，我们创建了一个基于果蝇翼神经束的新型神经损伤活体动物模型。在本项目中，我们计划运用这一模型结合高通量细胞筛选实验，全面、系统化地揭示介导Nmnat神经保护功能的上游调节机制和下游作用分子，以此深入研究生物体内调控神经轴突退化变性坏死的分子机理，并为研制和开发治疗神经损伤和神经退行性疾病的新型药物奠定基础。

Axonal degeneration is the pivotal pathological event of acute traumatic neural injury as well as many chronic neurodegenerative diseases. It is an active, highly regulated cellular program. For example, upregulation of nicotinamide mononucleotide adenosyltransferase (Nmnat) can significantly delay axonal degeneration. Moreover, we have recently found that knockdown of Nmnat led to spontaneous axonal degeneration in vivo, indicating that the endogenous Nmnat gene plays an essential role in maintaining axonal integrity. Nevertheless, little is known about the molecular mechanism of Nmnat's neuroprotective function. We have recently developed a novel in vivo model of nerve injury based on the Drosophila wing axon (DWA). In this study, we plan to use this DWA model combined with cell-based high-throughput screening to carry out a comprehensive and systematic study to reveal the upstream regulatory mechanism and downstream targets that mediate Nmnat's neuroprotective function. By such study, we hope to discover the key genes and core mechanisms regulating axonal degeneration and to provide the foundation for developing new drugs for treating neural injury and neurodegenerative diseases.