Reprogramming Strategies of Promoting Optic Nerve Regeneration and Vision Restoration

促进视神经再生和视力恢复的重编程策略

• 批准号: 9322464
• 负责人: ZHIGANG HE
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322464
• 关键词: Adult; Anatomy; Axon; Biological Assay; Blindness; Brain; Candidate Disease Gene; Cells; Circadian Rhythms; Development; Exhibits; Eye; FRAP1 gene; Genetic Transcription; Growth; IGF1 gene; Label; Light; Methods; Modeling; Molecular; Mus; Natural regeneration; Optic Nerve; Optic Nerve Injuries; PTEN gene; Pathway interactions; Photosensitivity; Pilot Projects; Proteins; Recovery of Function; Research; Retinal Ganglion Cells; SOX11 gene; SOX4 gene; Stem Cell Research; Technology; Vision; Visual Pathways; axon regeneration; base; behavior test; circadian pacemaker; combinatorial; experimental study; functional outcomes; functional restoration; improved; induced pluripotent stem cell; injured; insight; melanopsin; nerve supply; neuronal survival; novel; novel strategies; optic nerve regeneration; osteopontin; overexpression; prevent; regenerative; restoration; retinal progenitor cell; suprachiasmatic nucleus; transcription factor; visual information

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.

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， 导致视力丧失因此，我们的研究一直集中在开发方法，以促进有效的 视神经轴突再生和重建功能性视觉通路。最近的研究表明， 开发了几种刺激轴突再生的新策略，然而，这些方法中的每一种 仅在视网膜神经节细胞（RGC）的亚群中实现再生。因此，为了恢复视力， 是迫切需要的，以促进再生的多种类型的RGC。灵感来自于 为了获得iPS细胞，我们假设过表达某些转录， 成人RGC中的因子可以将它们重编程为类似于RGC的生长能力状态。为此我们 我已经筛选了一系列在分化过程中正常表达的转录因子 阶段的视网膜祖细胞，以检查哪一个（S），当在成人RGC中过表达时，可以使 使用眶内视神经损伤模型的显著轴突再生。有趣的是，我们发现， 转录因子Sox 11和Sox 4在较小程度上的表达导致了明显的视神经损伤。 再生初步分析显示，Sox 11的作用可能不同于由 PTEN缺失（参见方法）。此外，虽然PTEN缺失可选择性地促进细胞的再生， α型RGCs，Sox11过表达促进黑视素表达的再生 光敏RGC（ipRGC）和其他未确定类型的RGC。这些初步发现表明， 通过恢复Sox 11表达促进视神经再生的新原理。在此，我们建议 探索Sox 11刺激RGC轴突再生的潜在机制及其潜力 应用，无论是本身或与其他组合，在实现功能恢复。