The Molecular Basis Underlying Optic Nerve Growth in Development and Regeneration

 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，这对恢复患有视神经损伤或疾病（包括青光眼）的患者的视力提出了重大挑战。因此，这些患者在其余生中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。然而，深入了解分子 控制视神经生长/再生的基础仍然不明确。我们在这里提出调查为什么视神经不能再生，以及如何可以增强神经再生，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，其关闭对视神经再生的失败至关重要。我实验室最近发现了一种新的有效调节剂，胰岛素样生长因子（IGF结合蛋白样1（IGFBPL 1）），其存在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-1 R）及其下游信号的激活。外源性IGFBPL 1的管理促进视神经再生和RGC的存活在成年小鼠，而IGF-1 R诱导的信号，至少在文化，取消IGFBPL 1介导的轴突生长或再生的封锁。这表明IGFBPL 1通过IGF-1 R诱导的细胞内事件发挥作用以调节视神经再生。重要的是，IGFBPL 1作为一种分泌因子，为损伤后操纵神经再生和恢复视力提供了一种临床可行的候选者 在人类身上。因此，该提议旨在进一步探索IGFBPL 1通过其促进RGC轴突再生的潜在机制，特别是其与IGF-1 R介导的信号的关系。此外，将在建立的视神经损伤动物模型中评估IGFBPL 1促进视神经再生的功效。完成拟议的研究将揭示IGF-1 R介导的级联反应中一个以前未知的信号环，调节RGC轴突生长，并将促进我们对控制视神经再生和修复机制的理解。这将加速一种新的再生疗法的临床前开发，用于目前无法治疗的疾病。由于视神经长期以来一直是研究CNS损伤的标准模型，因此结果也可能对治疗脑和脊髓损伤或疾病的新疗法的开发产生广泛影响。

 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.