Rewiring the Injured Brain with GABA Progenitors

用 GABA 祖细胞重新连接受损的大脑

• 批准号: 10211616
• 负责人: Robert F Hunt
• 金额: $ 45.16万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211616
• 关键词: Acute; Address; Adolescent; Adult; American; Anxiety; Area; Behavior; Behavioral; Behavioral Assay; Benchmarking; Brain; Brain Injuries; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinic; Closed head injuries; Cognitive; Craniocerebral Trauma; Development; Disease; Electroencephalography; Electrophysiology (science); Embryo; Epilepsy; Fluorescent Antibody Technique; Funding; Ganglia; Generations; Goals; Hippocampus (Brain); Human; Image; Impairment; In Vitro; Injections; Injury; Interneurons; Laboratories; Light; Long-Term Effects; Medial; Memory; Memory impairment; Modeling; Monitor; Motor; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Output; Patients; Pattern; Post-Traumatic Epilepsy; Pre-Clinical Model; Procedures; Property; Replacement Therapy; Research; Rodent; Rodent Model; Seizures; Slice; Source; Supportive care; Synapses; TBI treatment; Technology; Therapeutic; Therapeutic Effect; Tissues; Translating; Transplantation; Traumatic Brain Injury; Treatment Efficacy; Viral; Work; cell type; clinically relevant; controlled cortical impact; cost; design; disability; gamma-Aminobutyric Acid; human pluripotent stem cell; improved; induced pluripotent stem cell; inhibitory neuron; migration; mouse model; nerve stem cell; nervous system disorder; neural circuit; novel therapeutics; optogenetics; patch clamp; prevent; progenitor; side effect; stem cells; synaptic inhibition; therapeutic evaluation

Abstract Transplantation of neural progenitor cells has extraordinary potential for the treatment of many nervous system disorders. Several recent studies have shown that progenitor cells derived from the embryonic mouse medial ganglionic eminence (MGE) retain a unique ability to migrate and differentiate into GABAergic interneurons following transplantation into the juvenile or adult rodent brain. We recently demonstrated that these cells are effective in correcting memory impairments and preventing spontaneous seizures in a mouse model of traumatic brain injury. However, it is not known whether similar therapeutic effects can be achieved with clinically-relevant cell sources, such as human pluripotent stem cells. Here, we propose studies to evaluate the effect of human-derived interneurons in a pre-clinical model of traumatic brain injury. Our approach involves transplantation of human interneuron progenitors into a widely-used rodent model of closed-head injury at different stages following injury followed by in vitro patch-clamp recordings, immunofluorescence techniques and neural circuit mapping to evaluate the synaptic integration of grafted neurons. A battery of behavioral assays and video-EEG monitoring will also be applied. Two specific aims are proposed: (i) determine how human-derived GABA progenitors integrate into brain injured hippocampus, and (ii) test the therapeutic efficacy of human GABA neurons in a mouse model of traumatic brain injury. If successful, our results will help move these exciting technologies closer to the clinic by establishing relatively direct proof of concept for human interneuron transplantation to treat traumatic brain injury.

摘要 神经前体细胞移植在许多神经系统疾病的治疗中具有非凡的潜力 紊乱最近的几项研究表明，来自胚胎小鼠中膜的祖细胞， 神经节隆起（MGE）保留了迁移和分化为GABA能中间神经元的独特能力 移植到幼年或成年啮齿动物脑中后。我们最近证明了这些细胞是 有效地纠正记忆障碍和预防自发性癫痫发作的小鼠模型， 创伤性脑损伤然而，目前尚不清楚是否可以实现类似的治疗效果， 临床相关的细胞来源，如人多能干细胞。在这里，我们提出研究，以评估 人源性中间神经元在创伤性脑损伤临床前模型中的作用。我们的方法包括 将人中间神经元祖细胞移植到广泛使用的闭合性头部损伤的啮齿动物模型中， 损伤后的不同阶段，随后进行体外膜片钳记录，免疫荧光技术 和神经回路映射以评估移植神经元的突触整合。一系列的行为 还将应用分析和视频EEG监测。提出了两个具体目标：（一）确定如何 人源性GABA祖细胞整合入脑损伤的海马，和（ii）测试治疗性GABA祖细胞 人GABA神经元在创伤性脑损伤小鼠模型中的功效。如果成功，我们的研究结果将有助于 通过为人类建立相对直接的概念验证， 中间神经元移植治疗脑外伤