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（由适用提供）：成年人的视神经几乎没有再生或自我修复的潜力，这对恢复视神经损伤或疾病（包括青光眼）患者的视力构成了重大挑战。因此，这些患者在余生中遭受了患者的后果和视力丧失。再生疗法对于保护视力或逆转视力丧失至关重要。然而深入了解分子 控制视神经生长/再生的基础仍然模棱两可。我们在这里建议研究为什么视神经无法再生以及如何增强神经再生以改善受伤后神经元功能。我和其他实验室的长期工作表明，视神经的增长是开发过程中的一个编程事件，其关闭对视神经再生的失败产生了巨大贡献。我实验室中最近的发现确定了一种新型的有效调节剂，胰岛素样生长因子（IGF结合蛋白（例如1（IGFBPL1）），其存在激活了视网膜神经节细胞（RGC）轴突（RGC）轴突（RGC）轴突的再生过程，并诱导IGF-1受体的激活IGF-1受体（IGF-1R）及其下层exemant signals Indercantial signals。成年小鼠的再生和RGC的生存；至少在培养物中，IGF-1R诱导的信号取消了IGFBPL1介导的轴突生长或再生的重生。可行的候选人，以操纵神经再生和恢复受伤后的视力 在人类中。因此，该建议旨在进一步探索IGFBPL1（尤其是其与IGF-1R介导的信号的关系）促进RGC轴突再生的潜在机制。此外，它将评估IGFBPL1在既定的视神经损伤动物模型中促进视神经再生的有效性。拟议研究的完成将在调节RGC轴突生长的调节中发现以前未知的信号循环，并将促进我们对控制视神经再生和修复机制的理解。这将加快针对目前不可治疗的疾病的新型再生疗法的临床前发展。由于长期以来一直是研究中枢神经系统损伤研究的标准模型，因此结果也可能对治疗脑和脊髓损伤或疾病的新疗法产生广泛的影响。