Autonomous Optogenetic Inhibition of Epileptic Activity Using a Bioluminescent Li

使用生物发光锂自主光遗传学抑制癫痫活动

• 批准号: 8464291
• 负责人: ROBERT E GROSS
• 金额: $ 29.21万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464291
• 关键词: Address; Alternative Therapies; Automobile Driving; Biological; Biological feedback; Bioluminescence; Calcium; Cells; Cerebrospinal Fluid; Clinic; Clinical; Collaborations; Dose; Electric Stimulation; Electrodes; Epilepsy; Excision; Face; Feedback; Genes; Goals; Halorhodopsins; Heating; Hippocampus (Brain); Image; Implant; In Vitro; Injury; Institutes; Ion Channel; Laboratories; Lasers; Light; Luciferases; Measures; Microscopy; Modeling; Neurologic; Neurons; Operative Surgical Procedures; Opsin; Patients; Pharmacotherapy; Photons; Population; Published Comment; Pump; Refractory; Reporter; Reporting; Research; Resistance; Risk; Scheme; Seizures; Solutions; Source; Specificity; System; Techniques; Technology; Testing; Therapeutic; Translating; Translations; Work; absorption; alternative treatment; base; bench to bedside; biological systems; cell type; disability; flexibility; high risk; hippocampal pyramidal neuron; in vitro Model; in vivo; in vivo Model; inhibitory neuron; innovation; nervous system disorder; neuroregulation; novel; novel strategies; optical imaging; optogenetics; prevent; relating to nervous system; research study; sensor; success; tool

DESCRIPTION (provided by applicant): Approximately 20-40% of patients with epilepsy have refractory seizures unresponsive to pharmacotherapy. There is therefore a need to develop alternative treatments for this large population of people who are at higher risk of developing epilepsy-related disabilities. Optogenetics - which provides a powerful approach to excite and/or inhibit neural activity in a cell-type specific manner - possesses great potential to limit or abolish the spread of the pathological neural activity underlying epileptic seizures. Despite this therapeutic potential, the use of optogenetics faces many technical challenges that limit its usefulness and translatability to the clinical setting. In this proposal, we present a hihly innovative solution to these problems by combining the use of optogenetics with bioluminescent reporters. Calcium-sensitive luciferases are a kind of bioluminescent reporter that has been successfully used for imaging neural activity in vivo. These luciferases respond to depolarization-associated calcium influx by emitting light that is compatible with the absorption spectrum of various inhibitory light-sensitive ion channels. We propose to use these reporters to create what we term an autonomous biologic controller capable of driving optogenetic feedback to control pathological activity. In our proposed model, calcium-sensitive luciferases would report neural activity in the form of light, inhibitory opsins would be activated by the emitted liht, and propagation of activity would be inhibited as the cell is hyperpolarized by the opsin. This autonomous, biological feedback of epileptic activity provides a novel solution to the technical limitations of optogenetics by eliminating the need for an external light source and offering a means for autonomous closed-loop feedback control. We suggest that this research is highly innovative and has the potential of accelerating the use of optogenetics as a tool to develop new therapies for epilepsy.

描述（由申请人提供）：大约 20-40% 的癫痫患者患有对药物治疗无反应的难治性癫痫发作。因此，需要为这一大量罹患癫痫相关残疾风险较高的人群开发替代疗法。光遗传学 - 它提供了一种以细胞类型特定方式激发和/或抑制神经活动的强大方法 - 具有巨大的潜力 限制或消除癫痫发作背后的病理神经活动的传播。尽管具有这种治疗潜力，但光遗传学的使用面临许多技术挑战，限制了其在临床环境中的实用性和可转化性。在这项提案中，我们通过将光遗传学与生物发光报告基因相结合，提出了针对这些问题的高度创新的解决方案。钙敏感荧光素酶是一种生物发光报告基因，已成功用于体内神经活动成像。这些荧光素酶通过发射与各种抑制性光敏离子通道的吸收光谱兼容的光来响应与去极化相关的钙流入。我们建议使用这些记者来创建我们所说的自主生物控制器，能够驱动光遗传学反馈来控制病理活动。在我们提出的模型中，钙敏感荧光素酶将以光的形式报告神经活动，抑制性视蛋白将被发射的光激活，并且当细胞被视蛋白超极化时，活动的传播将被抑制。这种癫痫活动的自主生物反馈通过消除对外部光源的需要并提供自主闭环反馈控制的手段，为光遗传学的技术限制提供了一种新颖的解决方案。我们认为这项研究具有高度创新性，有可能加速利用光遗传学作为开发癫痫新疗法的工具。