The Molecular Basis Underlying Optic Nerve Growth in Development and Regeneration

视神经发育和再生生长的分子基础

• 批准号: 9113192
• 负责人: Dong Feng Chen
• 金额: $ 49.25万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113192
• 关键词: Address; Adult; Animal Model; Axon; Binding; Birth; Blindness; Brain; Cell Survival; Clinical; Complex; Development; Disease; Event; Failure; Gene Expression; Genetic Programming; Glaucoma; Goals; Growth; Human; IRS2 gene; In Vitro; Injury; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor-Binding Proteins; Laboratories; Lead; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Natural regeneration; Nature; Nerve; Nerve Fibers; Nerve Regeneration; Neurodegenerative Disorders; Neurons; Optic Nerve; Optic Nerve Injuries; Pathway interactions; Patients; Pharmacotherapy; Process; Quality of life; Regulation; Research; Rest; Retinal Ganglion Cells; Role; Signal Transduction; Somatomedins; Study models; Testing; Vision; Work; axon growth; axon regeneration; base; central nervous system injury; experience; functional restoration; improved; in vivo; innovation; knock-down; member; nerve injury; novel; novel therapeutics; optic nerve regeneration; pre-clinical; prevent; programs; public health relevance; receptor; receptor-mediated signaling; regenerative; regenerative agent; regenerative therapy; relating to nervous system; repaired; secretory protein; spinal cord and brain injury; therapeutic target; transcriptome sequencing

 DESCRIPTION (provided by applicant): The optic nerve of adult humans shows little potential for regeneration or self-repair, which presents a major challenge to restoring vision in patients with optic nerve injury or diseases, including glaucoma. These patients thus suffer from the pathological consequences and vision loss for the rest of their lives. A regenerative therapy is vital for preserving sight or reversing vision loss. Yet an in depth understanding of the molecular basis that controls optic nerve growth/regeneration remains ambiguous. We here propose to investigate why the optic nerve fails to regenerate and how nerve regeneration can be enhanced to improve neuronal function after injury. Long-standing work from my and other laboratories has shown that optic nerve growth is a programed event during development whose shut-down contributes critically to the failure of optic nerve regeneration. A recent discovery in my laboratory has identified a novel potent regulator, insulin-like growth factor (IGF binding protein like 1 (IGFBPL1) whose presence activates the growth program and regenerative process of retinal ganglion cell (RGC) axons and induces activation of IGF-1 receptor (IGF-1R) and its downstream signals. Administration of exogenous IGFBPL1 promoted optic nerve regeneration and RGC survival in adult mice; whereas, blockade of IGF-1R-induced signals, at least in culture, abolished IGFBPL1-mediated axonal growth or regeneration. This points to a central role for IGFBPL1 functioning through IGF-1R-induced intracellular events to regulate optic nerve regeneration. Importantly, IGFBPL1 as a secretory factor presents a clinically feasible candidate for manipulating nerve regeneration and restoring vision after injury in humans. This proposal thus seeks to further explore the underlying mechanisms through which IGFBPL1, particularly its relation to IGF-1R-mediated signals, promotes RGC axon regeneration. Moreover, it will evaluate the efficacy of IGFBPL1 on promoting optic nerve regeneration in an established animal model of optic nerve injury. Completion of the proposed studies will uncover a previously unknown signaling loop in IGF-1R-mediated cascades in the regulation of RGC axon growth and will advance our understanding of the mechanisms that control optic nerve regeneration and repair. This will accelerate the preclinical development of a novel regenerative therapy for currently untreatable conditions. As the optic nerve has long served as a standard model for the study of CNS injury, results may also have a broad impact on the development of new therapies to treat brain and spinal cord injury or diseases.

 描述（由申请人提供）：成年人的视神经几乎没有再生或自我修复的潜力，这对患有视神经损伤或疾病（包括青光眼）的患者恢复视力提出了重大挑战。因此，这些患者的余生都会遭受病理后果和视力丧失。再生疗法对于保持视力或逆转视力丧失至关重要。对分子的深入了解 控制视神经生长/再生的基础仍然不明确。我们在此提出研究视神经无法再生的原因以及如何增强神经再生以改善损伤后的神经元功能。我和其他实验室的长期工作表明，视神经生长是发育过程中的一个程序化事件，其停止是导致视神经再生失败的关键因素。我实验室最近的一项发现发现了一种新型强效调节剂——胰岛素样生长因子（IGF 结合蛋白样 1 (IGFBPL1)），其存在可激活视网膜神经节细胞 (RGC) 轴突的生长程序和再生过程，并诱导 IGF-1 受体 (IGF-1R) 及其下游信号的激活。外源性 IGFBPL1 的施用可促进视神经的生长 成年小鼠的再生和 RGC 存活；然而，阻断 IGF-1R 诱导的信号（至少在培养物中）会消除 IGFBPL1 介导的轴突生长或再生。这表明 IGFBPL1 通过 IGF-1R 诱导的细胞内事件调节视神经再生发挥核心作用。重要的是，IGFBPL1 作为一种分泌因子在临床上表现出 损伤后操纵神经再生和恢复视力的可行候选者 在人类中。因此，该提案旨在进一步探索 IGFBPL1 促进 RGC 轴突再生的潜在机制，特别是其与 IGF-1R 介导的信号的关系。此外，还将在已建立的视神经损伤动物模型中评估 IGFBPL1 促进视神经再生的功效。完成拟议的研究将揭示 IGF-1R 介导的 RGC 轴突生长调节级联中以前未知的信号环路，并将增进我们对控制视神经再生和修复机制的理解。这将加速针对目前无法治疗的疾病的新型再生疗法的临床前开发。由于视神经长期以来一直作为研究中枢神经系统损伤的标准模型，因此研究结果也可能对治疗脑和脊髓损伤或疾病的新疗法的开发产生广泛的影响。