Rebuilding visual functional connections

重建视觉功能连接

• 批准号: 9239819
• 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: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239819
• 关键词: 4-Aminopyridine; Acute; Address; Adult; Adverse effects; Animal Model; Axon; Behavioral; Binding; Brain-Derived Neurotrophic Factor; Cell Adhesion Molecules; Ciliary Neurotrophic Factor; Conflict (Psychology); Defect; Degenerative Disorder; Exhibits; Extracellular Protein; Failure; Funding; Glaucoma; Growth Factor; IGF1 gene; Impairment; Individual; Integrins; Intervention; Label; Lesion; Mediating; Molecular; Mus; Natural regeneration; Neural Conduction; Neurons; Oligodendroglia; Optic Nerve; Optic tract structure; Outcome; PTEN gene; Pathway interactions; Pharmacology; Potassium Channel Blockers; Process; Proliferating; Recombinant Proteins; Recovery; Recovery of Function; Retinal Ganglion Cells; Signal Transduction; Surface; Testing; Therapeutic; Traumatic injury; Treatment Efficacy; Vision; Visual; axon regeneration; axonal degeneration; cell type; experimental study; functional improvement; functional restoration; improved; injured; insight; myelination; neurotransmission; oligodendrocyte precursor; optic nerve regeneration; osteopontin; overexpression; prevent; receptor; regenerative; repaired; response; restoration; retinal axon

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.

项目概要 视神经中视网膜神经节细胞 (RGC) 衍生的轴突受损或变性 解释了创伤性损伤或退行性疾病（例如青光眼）后的视觉功能缺陷。 因此，合理的修复策略是促进受损的视神经轴突在病变部位再生， 与他们的目标重新建立联系。在上一个资助期间，我们在优化方面取得了重大进展 促进再生的策略。我们首先发现 PTEN 和 SOCS3 的共缺失导致了稳健的 轴突再生。我们的进一步研究表明骨桥蛋白（OPN）、IGF1和CNTF的过度表达 可以模拟 PTEN 和 SOSC3 共缺失的效果，导致类似程度的轴突再生。 然而，这种再生的轴突无法重新髓鞘化，从而阻止视力恢复，除非钾通道 迅速施用阻滞剂以允许神经元信号的轴突传导。由于 OPN/IGF1/CNTF 都是 可以生产细胞外蛋白和重组蛋白，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。为进一步将其发展成为 有效的治疗策略，我们需要解决以下问题：OPN/IGF1/CNTF能否联合 刺激所有类型的 RGC 再生轴突？再生的轴突投射到正确的目标吗？怎么可以 可以诱导髓鞘再生吗？使用视神经和视路再生动物模型，我们将解决 每个问题都希望揭示这些过程的关键细胞和分子调节剂。我们期望 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。