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 到目前为止，还没有治疗方法可以恢复全世界6400多万因疾病而失明的人的视力。 会损伤视神经虽然目前再生视神经的方法已经成功地引导了长时间的视神经损伤， 远距离轴突再生，这些策略仍然受到以下事实的限制：1）功效通常已被证明 当在轴突损伤之前开始治疗时，其临床应用有限; 2）它们可能具有以下风险： 肿瘤转化，因此可能不容易预防性部署;和3）脱靶轴突的发生率 再生，表明不仅需要促进轴突生长的信号，而且需要指导轴突生长的信号， 预定目标。我们在电气工程师，神经科学家，电生理学家， 和神经外科医生已经收集了令人信服的初步数据，证明外源性应用 电场（EF）控制体外视网膜神经节细胞（RGC）轴突生长的方向。在体内，用 不对称波形被发现在指导全长视神经再生方面是有效的，没有证据表明 异常靶向，恢复部分视觉功能（上级丘和模式中的局部场电位记录 视网膜电图（electroretinogram）。有趣的是，对称波形的刺激在促进 RGC存活率高于非对称波形。发现不同的波形（不对称与对称）可能 激活控制不同细胞行为的不同信号通路提供了评估 联合刺激的协同效应。在这里，我们建议比较联合对称和 不对称EF刺激对恢复视觉功能的作用优于单独治疗。此外，虽然EF刺激 不对称波形的成功恢复了部分视觉功能， 上级丘较正常人低，宽丘较正常人长。这种功能障碍是否源于无效 RGC突触传递（空间总和）或缺乏髓鞘（时间总和）或两者都是未知的。这里我们 建议采用免疫组织化学、跨突触病毒标记技术和电生理学实验， 询问这种信号缺陷的来源。如果成功的话，这里提出的实验有可能推进 EF应用到一种策略中，当与其他RGC轴突再生方法协同应用时，可以帮助 使视神经再生，恢复视神经病变致盲患者的视功能。