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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结