Elucidating Neuron-Intrinsic Molecular Mechanisms of Optic Nerve Regeneration

 描述(申请人提供)：由于中枢神经系统(CNS)轴突再生失败，成熟的中枢神经系统(CNS)轴突损伤导致生命功能丧失。中和细胞外抑制分子只能在体内产生有限的再生或功能恢复， 这表明神经元内在因素起着关键作用。由于PTEN/mTOR通路对中枢神经系统轴突再生至关重要，了解该通路的再生控制是开发新的神经损伤治疗方法的第一步。不幸的是，mTOR过度活跃会导致肿瘤形成、代谢性疾病和神经系统疾病。因此，至关重要的是要确定具体的 PTEN/mTOR促进轴突再生的下游效应器，并将它们与介导mTOR有害效应的其他靶点隔离。利用视网膜神经节细胞和视神经作为中枢神经系统损伤模型的解剖学和技术优势，我们已经确定了轴突生长的关键调控因子，现在可以理想地阐明PTEN/mTOR刺激成熟中枢神经系统轴突再生的下游机制，并确定PTEN/mTOR调控成年CNS轴突再生的翻译靶点。这些效应器是促进中枢神经系统损伤和疾病再生的理想治疗靶点，可以选择性地激活，而不激活其他潜在的有害途径，从而帮助安全地将我们的发现转化为新的神经修复疗法，以保护中枢神经系统损伤患者的生命功能。

 DESCRIPTION (provided by applicant): Injuries of mature central nervous system (CNS) axons result in loss of vital functions due to the failure of CNS axons regeneration. Neutralizing extracellular inhibitory molecules yields only limited regeneration or functional recovery in vivo, suggesting a critical role for neuron-intrinsic factors. As it has become apparent that the PTEN/mTOR pathway is critical for CNS axon regeneration, understanding the regrowth control of this pathway represents the first step toward developing novel therapeutic approaches to neural injury. Unfortunately, mTOR over-activity can result in tumor formation, metabolic diseases, and neurological disorders. It is therefore critically important to identify the specific downstream effectors by which PTEN/mTOR promotes axon regeneration, and to isolate them from other targets that mediate mTOR's deleterious effects. Using the anatomical and technical advantages of retinal ganglion cell and optic nerve as a CNS injury model, we have identified crucial regulators of axon growth, and are now ideally positioned to elucidate the downstream mechanisms by which PTEN/mTOR stimulates regeneration in mature CNS axons and identify translational targets of PTEN/mTOR govern adult CNS axon regeneration. These effectors are ideal therapeutic targets to promote regeneration in CNS injury and diseases, which can be selectively activated without activating other, potentially harmful pathways, thus to assist in safely translating our findings into novel neural repair treatments to preserve vital functions in patients with CNS injuries.