中枢神经系统神经元的轴突在损伤后不具有修复和再生的能力，从而造成外伤后瘫痪、失语等永久性功能丧失。目前主要通过提高受损神经元轴突的生长能力(内因)和抑制导致影响轴突再生甚至致其退缩的胶质疤痕来源的外源因子(外因)两方面来研究中枢神经元轴突再生，然而靶向单因素的治疗策略在临床上均告失败，因此申请人提出以Lgl1-aPKC通路为靶标，同时改变内外两个因素，在促进Lgl1介导的轴突再生的同时，阻断aPKC介导的外源抑制，来最大化地促进轴突的再生。申请人通过利用体外微流动轴突损毁模型，实现了对中枢神经轴突再生的精确监控，并发现aPKC对Lgl1的磷酸化失活会引起轴突退缩，而Lgl1的持续激活则可以显著促进轴突再生。并结合多种中枢神经损伤的经典模型，利用小肽Tat-Lgl1或腺病毒感染持续激活动物体内的Lgl1，进一步验证靶向Lgl1-aPKC在神经再生过程中的作用。

In mammalian central nervous system (CNS), axon is incapable to repair and regeneration after injury, which is the underlying pathological mechanism for permanent functional loss such as paralysis, aphasia caused by traumatic brain or spinal injury. There are two major factors that prevent axon regeneration in CNS neurons: 1) Injured CNS axons have extremely low innate growth capacity; 2) Glial scar-derived exogenous factors inhibit the axon regrowth and cause rapid axon withdrawal. However, so far all therapeutic strategies targeting single factor have failed clinically. In this study, based on her previous study, the applicant proposed to target Lgl1-aPKC pathway to simultaneously administrate both intrinsic and extrinsic factors: by blocking the aPKC-mediated extrinsic inhibition while promoting Lgl1-mediated innate axon regrowth, to maximize axon regeneration. Applicants used the in vitro microfluidic-based axon injury models to precisely monitor the CNS axon regeneration. Using this model, it is found that aPKC phosphorylation and inactivation of Lgl1 caused axon retraction, whereas constitutive activation of Lgl1 significantly promote axon regeneration. Using a variety of classic models of CNS injury, the applicants will further define the role of Lgl1-aPKC pathway in promoting nerve regeneration by activate endogenous Lgl1 in mice CNS using small peptides Tat-Lgl1 or adenovirus infection.