New Approach to promote optic nerve regeneration and vision restoration

描述(申请人提供)：视神经损伤和再生障碍是创伤、青光眼和其他致盲疾病的主要特征。发展促进受损视神经解剖再生和功能重新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，表明在成人视网膜神经节细胞(RGC)中有条件地删除PTEN(磷酸酶和张力蛋白同系物)或TSC1(结节性硬化症1)可以使视神经损伤后强大的长距离轴突再生[1]，从而建立了第一个具有可重复性和强大的成年视神经再生的基因定义的小鼠模型。这项研究的目的有两个：进一步探索PTEN/TSC1缺失神经元中轴突再生的潜在机制，并确定再生的轴突是否能够重新形成突触连接并恢复失去的功能。我们期待从这些研究中获得的知识可以转化为新的治疗策略，促进视神经损伤、青光眼和其他类型眼病患者的功能恢复。 公共卫生相关性：我们最近发现PTEN或TSC1基因敲除促进了强大的视神经再生，这为研究使成年RGC轴突再生的细胞和分子机制提供了前所未有的机会。此外，这些基因定义的模型的可用使我们第一次能够在体内探索再生后事件，如轴突寻路、靶向、突触重新连接和行为恢复。这些研究应该为开发治疗策略以促进头部创伤、青光眼和其他与眼睛相关的疾病后轴突再生和视力恢复提供亟需的见解。

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.