Rewiring the injured brain with GABA progenitors.

用 GABA 祖细胞重新连接受伤的大脑。

• 批准号: 9215702
• 负责人: Robert F Hunt
• 金额: $ 33.8万
• 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 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215702
• 关键词: Acute; Address; Adolescent; Adult; Adverse effects; Alpha Cell; Alzheimer' s Disease; American; Animal Model; Animals; Anxiety; Area; Behavior; Behavioral; Behavioral Assay; Benchmarking; Brain; Brain Diseases; Brain Injuries; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinic; Closed head injuries; Cognitive; Comorbidity; Craniocerebral Trauma; Development; Disease; Electroencephalography; Electrophysiology (science); Embryo; Epilepsy; Exhibits; Fluorescent Antibody Technique; Frequencies; Ganglia; Generations; Goals; Health; Hippocampus (Brain); Human; In Vitro; Injury; Interneurons; Learning; Link; Long-Term Effects; Mechanics; Medial; Mediating; Memory; Methods; Modeling; Molecular; Monitor; Motor; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Output; Parkinson Disease; Patients; Pattern; Pharmacology; Phenotype; Population; Post-Traumatic Epilepsy; Procedures; Property; Recovery of Function; Replacement Therapy; Reporter; Reporting; Research; Rodent; Rodent Model; Seizures; Slice; Source; Stem Cell Research; Stem cells; Supportive care; Symptoms; Synapses; Technology; Temporal Lobe Epilepsy; Therapeutic; Tissues; Translating; Translations; Transplantation; Traumatic Brain Injury; Viral; Work; base; cell type; clinically relevant; controlled cortical impact; cost; design; disability; expectation; functional plasticity; gamma-Aminobutyric Acid; improved; induced pluripotent stem cell; inhibitory neuron; injured; migration; mouse model; nerve stem cell; nervous system disorder; neural circuit; novel; novel therapeutics; optogenetics; painful neuropathy; patch clamp; progenitor; public health relevance; response to injury

 DESCRIPTION (provided by applicant): 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 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 suppressing spontaneous seizures in a mouse model of epilepsy. However, the therapeutic potential of this approach remains largely unexplored for traumatic brain injury, a disorder characterized by interneuron cell loss and a number of health problems linked to neural circuit hyperexcitability (e.g., epilepsy). Here, we propose studies to develop a novel MGE transplantation therapy specifically designed to replace interneurons lost after traumatic brain injury. MGE cells will be transplanted into a widely-used rodent model of closed-head injury at different stages following injury. Our approach involves in vitro patch-clamp recordings, immunofluorescence techniques and neural circuit mapping to evaluate the synaptic integration of MGE- grafted interneurons. A battery of behavioral assays and video-EEG monitoring will also be applied. Two specific aims are proposed: (i) evaluate the synaptic integration of MGE cells grafted into brain injured hippocampus, and (ii) assess the therapeutic potential of MGE cell grafts in a mouse model of traumatic brain injury. If successful, our results will provide new information about the functional plasticity of MGE progenitors in the injured adult brain and would establish relatively direct proof of concept for interneuron transplantation to treat traumatic brain injury, particularly for conditions where loss of inhibition is a major contributor.

 描述（由申请人提供）：神经祖细胞移植对于治疗许多神经系统疾病具有非凡的潜力。最近的几项研究表明，来自胚胎内侧神经节隆起（MGE）的祖细胞在移植到幼年或成年啮齿动物脑中后保留了迁移和分化为GABA能中间神经元的独特能力。我们最近证明，这些细胞是有效的抑制自发性癫痫发作的小鼠模型。然而，这种方法的治疗潜力在很大程度上仍未被探索用于创伤性脑损伤，创伤性脑损伤是一种以中间神经元细胞损失和与神经回路过度兴奋相关的许多健康问题（例如，癫痫）。在这里，我们建议研究开发一种新的MGE移植疗法，专门用于取代创伤性脑损伤后丢失的中间神经元。MGE细胞将在损伤后的不同阶段移植到广泛使用的闭合性头部损伤的啮齿动物模型中。我们的方法包括体外膜片钳记录，免疫荧光技术和神经回路映射来评估MGE移植的中间神经元的突触整合。还将应用一系列行为分析和视频脑电图监测。提出了两个具体目标：（i）评估移植到脑损伤海马中的MGE细胞的突触整合，和（ii）评估MGE细胞移植物在创伤性脑损伤小鼠模型中的治疗潜力。如果成功，我们的成果 将提供关于受损成人脑中MGE祖细胞的功能可塑性的新信息，并将建立用于治疗创伤性脑损伤的中间神经元移植的相对直接的概念证明，特别是对于其中抑制丧失是主要贡献者的病症。