Reprogramming Strategies of Promoting Optic Nerve Regeneration and Vision Restoration

项目摘要 视神经轴突的损伤阻止了视觉信息从眼睛到大脑的传递，导致 为失明干杯。因此，我们的研究一直集中在开发方法来促进效率 视神经轴突再生和重建视功能通路。最近的研究导致了 几种刺激轴突再生的新策略的发展，然而每一种方法 仅在视网膜神经节细胞(RGC)亚群中获得再生。因此，为了恢复视力，新的战略 迫切需要促进多种类型视网膜节细胞的再生。受转录的启发 为了获得iPS细胞的重新编程技术，我们假设过度表达某些转录 成年视网膜节细胞中的因子可以将它们重新编程为年轻的视网膜节细胞样生长能力状态。为此，我们 已经对分化过程中正常表达的转录因子列表进行了筛选 视网膜祖细胞阶段，以检测哪一种(S)，当在成年视网膜节细胞中过表达时，可以使 使用眶内视神经损伤模型显著再生轴突。有趣的是，我们发现强迫 转录因子Sox11的表达，以及Sox4的较小程度，导致了明显的视神经 再生。初步分析显示，sox11的影响可能不同于 PTEN缺失(见方法)。此外，虽然PTEN缺失选择性地促进了来自 Alpha型视网膜节细胞，sox11过表达促进黑素表达的再生 光敏性视网膜节细胞(IpRGCs)和其他类型的视网膜节细胞。这些初步发现表明， 通过重建sox11表达促进视神经再生的新理论。在此，我们建议 探讨Sox11促进RGC轴突再生的潜在机制 应用程序本身或与其他应用程序结合使用，以实现功能恢复。

Project Summary The damage of optic nerve axons prevents the relay of the visual information from the eye to the brain, leading to the loss of vision. Therefore, our research has been focusing on developing methods to promote efficient optic nerve axon regeneration and to re-build functional visual pathways. Recent studies have led to the developments of several novel strategies that stimulate axon regeneration, however each of these methods only achieved regeneration in subsets of retinal ganglion cells (RGCs). Thus, to restore vision, new strategies are pressingly needed to promote regeneration of multiple types of RGCs. Inspired by the transcriptional reprogramming technology for obtaining iPS cells, we hypothesized that over-expressing certain transcription factors in adult RGCs could reprogram them into a young-RGC-like growth competent state. To this end, we have performed a screen for a list of transcription factors that are normally expressed during the differentiation stage of retinal progenitor cells, to examine which one(s), when overexpressed in adult RGCs, could enable significant axon regeneration using an intraorbital optic nerve injury model. Interestingly, we found that forced expression of the transcription factor Sox11, and to a less extent Sox4, resulted in marked optic nerve regeneration. Preliminary analysis revealed that the effects of Sox11 are likely different from those triggered by PTEN deletion (see Approach). Furthermore, while PTEN deletion promotes the regeneration selectively from alpha type of RGCs, Sox11 overexpression promotes the regeneration of melanopsin-expressing intrinsically photosensitive RGCs (ipRGCs) and other un-determined types of RGCs. These initial findings suggested a novel rationale for promoting optic nerve regeneration by reinstitute Sox11 expression. Here, we propose to explore the underlying mechanisms by which Sox11 stimulates RGC axon regeneration and its potential application, either by itself or in combination with others, in achieving functional recovery.