New Approach to promote optic nerve regeneration and vision restoration

描述（申请人提供）：视神经损伤和再生失败是创伤、青光眼和其他致盲疾病的主要特征。制定促进损伤视神经解剖再生和功能再连接的策略一直是一个长期的挑战。我们最近取得了一系列令人兴奋的发现，表明成人视网膜神经节细胞（RGCs）中PTEN（磷酸酶和紧张素同源物）或TSC1（结节性硬化症1）的条件缺失能够在视神经损伤后实现强大的长距离轴突再生(1)，从而建立了第一个具有可重复和强大的成人视神经再生的遗传定义小鼠模型。本研究的目的有两个：进一步探索PTEN/TSC1缺失神经元轴突再生的潜在机制，并确定再生的轴突是否可以重新形成突触连接并恢复失去的功能。我们期望从这些研究中获得的知识可以转化为新的治疗策略，以促进视神经损伤，青光眼和其他类型眼病患者的功能恢复。

DESCRIPTION (provided by applicant): Optic nerve damage and regeneration failure are major features of trauma, glaucoma, and other blinding diseases. Developing strategies to promote anatomical regeneration and functional re-connection of injured optic nerve has been a long-standing challenge. We recently made a set of exciting discoveries showing that conditional deletion of PTEN (phosphatase and tensin homolog) or TSC1 (tuberous sclerosis 1) in adult retinal ganglion cells (RGCs) enabled robust long-distance axon regeneration after optic nerve injury (1), thereby establishing the first genetically defined mouse models with reproducible and robust optic nerve regeneration in the adult. The objectives of this proposed study are two-fold: to further explore the underlying mechanisms permitting axon regeneration in PTEN/TSC1 deleted neurons and to determine whether the regenerating axons could re-form synaptic connections and restore lost functions. We expect that the knowledge obtained from these studies can be translated into novel therapeutic strategies to promote functional recovery in patients with optic nerve injury, glaucoma and other types of eye diseases. PUBLIC HEALTH RELEVANCE: Our recent findings that PTEN or TSC1 knockout promotes robust optic nerve regeneration provide an unprecedented opportunity to study the cellular and molecular mechanisms enabling adult RGC axons to regenerate. Furthermore, the availability of these genetically defined models allows us, for the first time, to explore post-regeneration events such as axon pathfinding, targeting, synaptic reconnection and behavioral recovery in vivo. These studies should provide much needed insights into developing therapeutic strategies to promote axon regeneration and vision restoration after head trauma, glaucoma and other eye-related diseases.