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会导致癫痫发作和认知合并症。使用抗惊厥药物进行全身治疗并不能充分控制癫痫发作，而且常常伴有严重的副作用，全球估计有 6500 万癫痫患者，其中约 30-40% 是药物难治性的。因此，需要新的疗法。光遗传学的最新进展表明，通过精确的细胞类型特异性定向控制神经活动可以抑制癫痫发作。虽然闭环光遗传学干预提供了识别网络以减少癫痫发作的策略，但植入光纤波导和转基因小鼠的使用排除了作为治疗工具的使用。为了克服与光遗传学作为临床模式相关的挑战，该提案将检验最近发现的超敏感和红移视紫红质（ChR）可以通过颅内和细胞类型特异性终止自发性、复发性癫痫发作的假设。该假设将通过开发非侵入性病毒靶向策略来测试，以限制这些新 ChR 的表达到治疗相关的中间神经元亚型，然后在皮层和海马局灶性癫痫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，以测试这种方法在野生型动物中的长期稳定性。对特定预测的进一步细化刺激将最大限度地减少脱靶效应。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性和可扩展性，这种经颅光遗传学平台将为治疗癫痫找到新的机会，并可能扩展到治疗其他神经系统疾病。 在拟议的研究和职业培训计划期间，我将得到系统神经科学、光遗传学、癫痫和行为动物模型、电生理学和计算分析方面经验丰富的专家团队的指导。该团队将通过新技术培训、手稿和资助写作、公开演讲、为学员提供建议以及在斯坦福大学巨大的科学环境中进行合作，为我的研究项目和专业发展提供建议，斯坦福大学提供了多个核心设施、职业发展中心和正式课程来支持我的工作。完成这个指导研究项目后，我将获得强大的技术和概念基础，将我的工程学背景与系统神经科学联系起来，我将利用它建立独立的研究生涯，开发和应用方法来研究神经系统疾病背后的神经机制，并为其开发治疗概念。