The Molecular Basis Underlying Optic Nerve Growth in Development and Regeneration

 描述(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)的患者恢复视力构成了重大挑战。因此，这些患者在其余生中遭受病理后果和视力丧失的痛苦。再生疗法对于保护视力或扭转视力丧失至关重要。然而对分子的深入了解 控制视神经生长/再生的基础仍然不明确。我们建议调查为什么视神经不能再生，以及如何加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性事件，它的关闭是导致视神经再生失败的关键因素。我的实验室最近发现了一种新的有效调节因子-胰岛素样生长因子(IGFBPL1)，它的存在激活了视网膜神经节细胞(RGC)轴突的生长程序和再生过程，并诱导了IGF-1受体(IGF-1R)及其下游信号的激活。给予外源性IGFBPL1促进成年小鼠视神经再生和RGC存活；然而，阻断IGF-1R诱导的信号，至少在培养中，取消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，为控制神经再生和恢复损伤后的视力提供了一个临床上可行的候选方案 在人类身上。因此，该建议试图进一步探讨IGFBPL1促进RGC轴突再生的潜在机制，特别是它与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上评估IGFBPL1促进视神经再生的效果。这些研究的完成将揭示IGF-1R介导的RGC轴突生长调控中的一个未知的信号环，并将促进我们对控制视神经再生和修复的机制的理解。这将加速目前无法治疗的疾病的新的再生疗法的临床前开发。由于视神经长期以来一直是研究中枢神经系统损伤的标准模型，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.