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，还没有任何治疗方法可以让世界各地因疾病而合法失明的恢复视力 这会损害视神经。尽管目前再生视神经的方法已经成功地引导Long 距离轴突再生，这些策略仍然受到以下事实的限制：1)有效性已被普遍证明 在轴突损伤之前开始治疗，这限制了临床应用；2)它们可能存在以下风险 肿瘤转化，因此可能不容易预防性部署；以及3)偏离靶点轴突的发生率 已有报道表明，再生不仅需要促进轴突生长的信号，还需要引导轴突生长的信号 预定目标。我们在电气工程师、神经科学家、电生理学家、 神经外科医生已经收集了令人信服的初步数据，证明了外源性应用 在体外，电场控制视网膜神经节细胞(RGC)轴突的生长方向。在体内，通过 非对称波形被发现在引导全长视神经再生方面有效，而没有证据表明 异常靶向，并恢复部分视觉功能(上丘和图案的局部场电位记录 视网膜电信号)挤压伤后。有趣的是，用对称波形刺激更有效地促进 RGC存活率高于非对称波形。发现不同的波形(不对称和对称)可能 激活控制不同细胞行为的不同信号通路为评估 来自复合刺激的协同效应。在这里，我们建议比较组合对称和 不对称EF刺激在恢复视功能方面优于单独的任何一种治疗。此外，虽然EF刺激 用不对称波形成功地恢复了部分视功能，局部场电位幅值在 上丘较正常对照组降低，潜伏期延长。这种功能障碍是否源于无效 RGC突触传递(空间总和)或髓鞘缺失(时间总和)或两者兼而有之尚不清楚。在这里，我们 建议使用免疫组织化学、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，这里提出的实验有可能取得进展 EF应用到一种策略，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，恢复视神经病致盲患者的视功能。