Rebuilding visual functional connections

项目摘要 视神经内视网膜神经节细胞（retinal ganglion cells，RGCs）轴突的损伤或变性 解释了创伤性损伤或退行性疾病如青光眼后的视觉功能缺陷。 因此，合乎逻辑的修复策略是促进受损的视神经轴突再生穿过病变， 重新联系他们的目标在上一个资助期内，我们在优化方面取得了重大进展， 促进再生的战略。我们首先发现，PTEN和SOCS 3的共缺失导致了稳定的细胞凋亡。 轴突再生我们进一步的研究表明，骨桥蛋白（OPN）、IGF 1和CNTF的过度表达， 可以模拟PTEN和SOSC 3共缺失的效果，导致类似程度的轴突再生。 然而，这种再生的轴突不能重新髓鞘化，除非钾通道被阻断，否则阻止视力的恢复。 阻断剂被急性施用以允许神经元信号的轴突传导。由于OPN/IGF 1/CNTF均为 胞外蛋白和重组蛋白可以生产，这种组合可能是最有前途的 刺激RGC轴突再生和视觉功能恢复的治疗。为了进一步发展成一个 有效的治疗策略，我们需要解决以下问题：OPN/IGF 1/CNTF能否联合应用 刺激所有类型的RGC再生轴突？再生的轴突能投射到正确的目标吗？怎么能 髓鞘再生会被诱导吗利用视神经和视束再生动物模型，我们将解决 这些问题中的每一个，希望揭示这些过程的关键细胞和分子调节因子。我们预计 所获得的结果可能为开发更有效和安全的治疗策略提供见解， 促进视力恢复。

PROJECT SUMMARY The damage or degeneration of the axons derived from the retinal ganglion cells (RGCs) in the optic nerve accounts for the visual functional defects after traumatic injury or degenerative diseases such as glaucoma. Thus, the logical repair strategy is to promote injured optic nerve axons to regenerate across the lesion and reconnect with their targets. In the previous funding period, we have made significant progress in optimizing regeneration-promoting strategies. We first discovered that co-deletion of PTEN and SOCS3 resulted in robust axon regeneration. Our further studies showed that over-expression of osteopontin (OPN) and IGF1 and CNTF could mimic the effects of co-deletion of PTEN and SOSC3, leading to similar extents of axon regeneration. However, such regenerated axons fail to re-myelinate preventing recovery of vision unless potassium channel blocker is acutely administered to allow axonal conduction of neuronal signal. Since OPN/IGF1/CNTF are all extracellular proteins and recombinant proteins can be produced, this combination may be the most promising treatment for stimulating RGC axon regeneration and vision function recovery. To further develop this into an effective therapeutic strategy, we need to address the following issues: can OPN/IGF1/CNTF combination stimulate all types of RGCs to regenerate axons? Do regenerated axons project to correct targets? How can re-myelination be induced? Using the optic nerve and optic tract regenerative animal model, we will address each of these questions, in a hope to reveal key cellular and molecular regulators these processes. We expect that the obtained results might provide insights into develop more effective and safe therapeutic strategies of promoting vision restoration.