Restoration of Optic Nerve Function Driven by In Vivo Multimodal Electrical Stimulation

体内多模式电刺激驱动视神经功能的恢复

• 批准号: 10720788
• 负责人: Kimberly K Gokoffski
• 金额: $ 59.8万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720788
• 关键词: Address; Adult; Aftercare; Anatomy; Animals; Area; Automobile Driving; Axon; Behavioral; Blinded; Brain; Cell Survival; Charge; Clinical; Collection; Crush Injury; Data; Dependence; Development; Disease; Dorsal; Electric Stimulation; Electrical Engineering; Electrodes; Electron Microscopy; Electrophysiology (science); Electroretinography; Eye; Functional disorder; Future; Growth; Growth Cones; Histologic; Hybrids; Immunohistochemistry; In Vitro; Incidence; Interdisciplinary Study; Investigation; Label; Lateral Geniculate Body; Legal Blindness; Length; Light; Location; Myelin; Natural regeneration; Nerve; Neurons; Neurosurgeon; Optic Nerve; Optic Nerve Transections; Optic tract structure; Patients; Pattern; Persons; Physiologic pulse; Potassium Channel Blockers; Rattus; Recovery; Recovery of Function; Regenerative response; Reporting; Research; Retinal Ganglion Cells; Risk; Signal Pathway; Signal Transduction; Source; Synapses; Synaptic Transmission; System; Techniques; Technology; Testing; Tissues; Translations; Viral; Vision; Visual; Work; axon growth; axon injury; axon regeneration; cell behavior; clinical application; combinatorial; comparative efficacy; diencephalon; electric field; experimental study; in vivo; inhibitor; interest; legally blind; multimodality; myelination; neoplastic; novel; optic nerve disorder; optic nerve regeneration; prophylactic; remyelination; response; restoration; retinal ganglion cell regeneration; sight restoration; stem; superior colliculus Corpora quadrigemina; transmission process; visual information; voltage

Project Summary To date, no therapy exists to restore vision to the over 64 million people worldwide who are legally blind from diseases that damage the optic nerve. Although current approaches for regenerating the optic nerve have successfully directed long distance axon regeneration, these strategies are still limited by the fact that 1) efficacy has generally been demonstrated when therapies were initiated before axon injury, which has limited clinical application; 2) they may carry a risk of neoplastic conversion and thus may not be readily deployed prophylactically; and 3) incidences of off target axon regeneration have been reported, indicating a need not just for signals that promote but also ones that direct axon growth to intended targets. Our multi-disciplinary collaboration between electrical engineers, neuroscientists, electrophysiologists, and neurosurgeons has enabled the collection of compelling preliminary data demonstrating that exogenously applied electric fields (EFs) control the direction of retinal ganglion cell (RGC) axon growth, in-vitro. In vivo, stimulation with asymmetric waveforms was found to be effective at directing full-length optic nerve regeneration, without evidence of aberrant targeting, and restoring partial visual function (local field potential recordings in the superior colliculus and pattern electroretinogram) after crush injury. Interestingly, stimulation with symmetric waveforms was more effective at promoting RGC survival than asymmetric waveforms. The discovery that different waveforms (asymmetric versus symmetric) may activate distinct signaling pathways that control different cellular behaviors provides a unique opportunity to assess for synergistic effects from combined stimulation. Here, we propose to compare the efficacy of combined symmetric and asymmetric EF stimulation on restoring visual function over either treatment alone. Additionally, although EF stimulation with asymmetric waveforms was successful at restoring partial visual function, local field potential amplitudes within the superior colliculus were lower and latencies longer than in normal controls. Whether this dysfunction stems from ineffective RGC synaptic transmission (spatial summation) or absence of myelin (temporal summation) or both is unknown. Here, we propose to employ immunohistochemical, transsynaptic viral labeling techniques, and electrophysiology experiments to interrogate the source of this signaling deficiency. If successful, experiments proposed here have the potential to advance EF application into a strategy that, when applied synergistically with other approaches for RGC axon regeneration, can help regenerate the optic nerve and restore visual function of patients blinded by optic neuropathies.

项目摘要 迄今 那会损害视神经。尽管目前的再生方法已成功地导向了长时间 距离轴突再生，这些策略仍然受到以下事实的限制，即1）疗效已被证明 当轴突受伤之前开始治疗时，临床应用有限； 2）他们可能会冒险 肿瘤转化，因此可能不容易预防。 3）关闭目标轴突的发生率 报道了再生，表明不仅需要促进的信号，而且还需要将轴突生长到 预期目标。我们的电气工程师，神经科学家，电生理学家之间的多学科合作， 神经外科医生已使引人入胜的初步数据收集，表明外源应用 电场（EFS）控制视网膜神经节细胞（RGC）轴突生长的方向。在体内，刺激 发现不对称波形在指导全长视神经再生方面有效，而没有证据表明 异常的靶向和恢复部分视觉功能（上丘和模式中的局部现场潜在记录 电图损伤后）。有趣的是，用对称波形刺激更有效地促进 RGC存活比不对称波形。发现不同波形（不对称与对称）的发现可能 激活控制不同蜂窝行为的不同信号通路为评估提供了独特的机会 联合刺激的协同作用。在这里，我们建议比较合并对称的功效和 仅在两种处理中恢复视觉功能的不对称EF刺激。另外，尽管EF刺激 由于不对称波形在恢复部分视觉功能方面取得了成功，局部场电位幅度在 上丘比在正常对照中较低，延迟时间更长。这种功能障碍是否源于无效 RGC突触传递（空间求和）或髓磷脂的不存在（时间求和）或两者都是未知的。在这里，我们 提议采​​用免疫组织化学，透射性病毒标记技术和电生理实验 询问此信号不足的来源。如果成功，此处提出的实验有可能进步 EF应用于一种策略，当与RGC轴突再生的其他方法协同应用时，可以帮助 再生视神经病盲目的患者的视神经和恢复视觉功能。