Noninvasive Optogenetic Interventions for Epilepsy

癫痫的无创光遗传学干预

• 批准号: 10400233
• 负责人: Ritchie Chen
• 金额: $ 12.23万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400233
• 关键词: Affect; Animal Model; Animals; Anterior Nuclear Group; Anticonvulsants; Behavior; Brain; Canis familiaris; Cerebellar Cortex; Cerebellum; Chronic; Cicatrix; Clinical; Cognitive; Collaborations; Computer Analysis; Core Facility; Coupling; Deep Brain Stimulation; Development; Devices; Electrodes; Electrophysiology (science); Engineering; Environment; Epilepsy; Fiber Optics; Focal Seizure; Foundations; Future; Gene Delivery; Generalized seizures; Gliosis; Goals; Grant; Hippocampus (Brain); Implant; Individual; Interneurons; Intervention; Intractable Epilepsy; Light; Location; Mammals; Manuscripts; Maps; Mentors; Methodology; Methods; Modality; Modeling; Motor Cortex; Mus; Neuraxis; Neurons; Neurosciences; Nucleus fastigii; Operative Surgical Procedures; Opsin; Optics; Output; Partial Epilepsies; Pathology; Patients; Penetration; Pharmaceutical Preparations; Phase; Play; Presynaptic Terminals; Proteins; Public Speaking; Purkinje Cells; Rattus; Recurrence; Refractory; Research; Research Personnel; Research Project Grants; Role; Seizures; Silicon Dioxide; Somatosensory Cortex; Specificity; System; Techniques; Technology; Testing; Therapeutic; Thick; Tissues; Training; Transgenic Mice; Universities; Viral; Work; Writing; biomaterial compatibility; career; career development; cell type; clinical translation; comorbidity; cranium; experience; experimental study; gene therapy; implantation; improved; light emission; light gated; motor control; mouse model; nanoparticle; nervous system disorder; neural circuit; neural implant; neural network; neuroinflammation; neuromechanism; neuroregulation; nonhuman primate; novel; novel therapeutics; optical fiber; optogenetics; photoactivation; relating to nervous system; side effect; superior colliculus Corpora quadrigemina; technique development; therapeutic target; therapy development; tool; treatment strategy; waveguide

In patients with epilepsy, central nervous system hyperexcitability and synchrony contribute to seizures and cognitive comorbidities. Systemic treatments with anticonvulsant drugs do not adequately control seizures and are often accompanied by severe side effects, where approximately 30-40% of the estimated 65 million epileptic patients worldwide are drug refractory. Consequently, new therapies are needed. Recent advances in optogenetics have demonstrated seizure suppression through precise cell type specific directional control of neural activity. While closed-loop optogenetic interventions provide strategies to identify networks to curtail seizures, the use of implanted fiber optic waveguides and transgenic mice precludes usage as a therapeutic tool. To overcome challenges associated with optogenetics as a clinical modality, this proposal will test the hypothesis that recently discovered supersensitive and red-shifted Channelrhodopsins (ChRs) can enable transcranial and cell type specific termination of spontaneous, recurrent seizures. The hypothesis will be tested by developing noninvasive viral-targeting strategies to restrict expression of these new ChRs to therapeutically- relevant interneuron subtypes followed by transcranial closed-loop optogenetic control in mouse models of focal epilepsy in the cortex and hippocampus. Chronic seizure suppression will be performed to test the long- term stability of this approach in wild-type animals. Further refining stimulation to specific projections will minimize off-target effects. By overcoming long standing hurdles of optogenetics, including invasiveness, viral- targeting of neural subpopulations, and scalability, this transcranial optogenetic platform will identify new opportunities for the treatment of epilepsy and may be extended to manage other neurological disorders. During the proposed research and career training plan, I will be mentored by an experienced team of experts in systems neuroscience, optogenetics, animal models of epilepsy and behavior, electrophysiology and computational analysis. This team will advise my research project and professional development through training in new techniques, manuscript and grant writing, public speaking, advising of mentees, and collaborations within the tremendous scientific environment at Stanford University, which offers several core facilities, career development centers, and formal coursework to support my work. Upon completion of this mentored research project, I will gain a strong technical and conceptual foundation to bridge my background in engineering with systems neuroscience, which I will use to establish an independent research career to develop and apply methods to study the neural mechanisms that underly neurological disorders and to develop treatment concepts for them.

在癫痫患者中，中枢神经系统过度兴奋和同步性有助于癫痫发作和认知合并症。抗惊厥药物的全身治疗不能充分控制癫痫发作，并且经常伴有严重的副作用，在全球估计的6500万癫痫患者中，约有30-40％是药物难治性。因此，需要新的疗法。光遗传学的最新进展通过神经活动的精确细胞类型的特定方向控制表明癫痫发作抑制。虽然闭环光遗传学干预措施提供了识别网络减少癫痫发作的策略，但使用植入的纤维波导和转基因小鼠的使用却排除了用法作为治疗工具。为了克服与光遗传学作为临床方式相关的挑战，该提案将检验以下假设：最近发现的超敏感和红移的通道旋转蛋白（CHRS）可以实现自发性，经常性癫痫发作的经颅和细胞类型终止。该假设将通过开发非侵入性病毒靶向策略来检验，以将这些新CHR的表达限制为治疗性与相关的中间神经元亚型，然后在皮质和海马室中局灶性癫痫的小鼠模型中进行经颅闭环光遗传学控制。将进行慢性癫痫发作抑制，以测试野生型动物中这种方法的长期稳定性。对特定预测的进一步完善刺激将最大程度地减少脱靶效应。通过克服光遗传学的长期障碍，包括侵入性，神经亚群的病毒靶向和可伸缩性，这种经颅遗传平台将确定治疗癫痫病的新机会，并可以扩展以管理其他神经系统疾病。 在拟议的研究和职业培训计划中，我将受到经验丰富的系统神经科学，光遗传学，癫痫和行为动物模型，电生理学和计算分析的专家团队的指导。该团队将通过培训新技术，手稿和赠款写作，公开演讲，对受训者的建议以及斯坦福大学的巨大科学环境中的合作来为我的研究项目和专业发展提供建议，该公司提供了几个核心设施，职业发展中心和正式的课程，以支持我的工作。完成这个指导的研究项目后，我将获得强大的技术和概念基础，以使用系统神经科学来弥合我的工程背景，我将使用该基础来建立独立的研究职业，以开发和应用方法来研究潜在的神经系统疾病并为其发展治疗概念的神经机制。