Treating Cortical Epilepsy with Interneuron Transplants

用中间神经元移植治疗皮质癫痫

• 批准号: 7356363
• 负责人: Stewart A Anderson
• 金额: $ 18.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356363
• 关键词: Address; Adult; Affect; Albumins; Antiepileptic Agents; Area; Attention; Award; Basic Science; Brain Injuries; Cell Count; Cell Therapy; Cell Transplants; Cells; Cerebral cortex; Chronic; Clinical; Consultations; Craniocerebral Trauma; Data; Development; Electrophysiology (science); Embryo; Epilepsy; Epileptogenesis; Event; Focal Seizure; Funding; Future; Goals; Grant; Human; Immigration; Interneurons; Intractable Epilepsy; Laboratories; Lead; Lesion; Light; Medical; Modeling; Molecular; Monitor; Mus; Neocortex; Neurology; Neurosciences; Neurosurgeon; Neurosurgical Procedures; Operative Surgical Procedures; Pan Genus; Personal Satisfaction; Pharmaceutical Preparations; Pharmacological Treatment; Physiological; Physiology; Postdoctoral Fellow; Prevention; Process; Prosencephalon; Protocols documentation; Psychiatry; Research; Research Personnel; Rodent Model; Role; Running; Scientist; Seizures; Source; Stem cells; Subgroup; Sum; Surgeon; System; Techniques; Telemetry; Testing; Tetanus Toxin; Translational Research; Transplantation; United States National Institutes of Health; Week; base; college; concept; density; design; in vivo; interest; migration; neocortical; optical imaging; postnatal; prevent; professor; progenitor

DESCRIPTION (provided by applicant): Despite advances in the treatment of seizure disorders, medically intractable epilepsy requiring surgical treatment remains a serious problem. The concept of treating seizures by grafting inhibitory interneurons into seizure foci is more than a decade old, but has yet to lead to clinically useful approaches. However, recent studies on the origins and specification of cortical interneurons warrant a new examination of this issue. We propose to use intracerebral grafts of interneuron precursors to treat chronic seizures that are focally induced in the adult mouse cortex. This study combines the expertise of two laboratories at Weill-Cornell Medical College. The PI, an Assistant Professor of Neurological Surgery, studies the propagation of cortical seizures in rodent models of epilepsy using in vivo electrophysiology and intrinsic optical imaging. The co-investigator, an Assistant Professor of Psychiatry, studies the specification of cortical interneuron subtypes in mice using transplantation of interneuron progenitors from the subcortical embryonic forebrain into the postnatal cortex. In Aim 1 the investigators will optimize the protocol for transplantation of interneuron progenitors into Tetanus Toxin (TTx)-induced chronic epileptic foci. In addition, effects of chronic seizures on interneuron migration, survival, and differentiation will be examined. Preliminary data suggest that, like transplants interneuron progenitors into the cortex of normal adult mice, transplants into TTx-induced seizure foci also result in migration, survival, and interneuronal differentiation of substantial numbers cells. Aim 2 will test the system-level functionality of transplanted interneurons by determining their ability to suppress epileptiform activity in the TTx model. Epileptiform activity will be assessed by simultaneous telemetry and video monitoring for several weeks before and several months following transplantation. The capacity to reduce epileptiform discharges with transplants of interneuron progenitor pools that are enriched for distinct interneuron subgroups will be compared to vehicle and cell-based controls. The results will strengthen the rationale for future studies using interneuron-progenitor directed stem cells, and also to explore the use of interneuron progenitors as a cell-based delivery system of anti-epileptic agents. The advances resulting from this proposal should inform efforts to prevent or interrupt intractable epileptogenesis resulting from focal lesions. The application of this research to increasingly clinically-oriented studies will be achieved by consultation with Dr. Theodore Schwartz, a practicing neurosurgeon who is the Director of Research at the Center for Epilepsy Surgery at WMC.

描述（由申请人提供）：尽管在癫痫疾病的治疗方面取得了进展，但需要手术治疗的医学难治性癫痫仍然是一个严重的问题。通过将抑制性中间神经元移植到癫痫病灶中治疗癫痫发作的概念已有十多年的历史，但尚未导致临床有用的方法。然而，最近对皮层中间神经元的起源和规范的研究，要求对这一问题进行新的检查。我们建议使用中间神经元前体脑内移植来治疗成年小鼠皮质局部诱导的慢性癫痫发作。这项研究结合了威尔-康奈尔医学院两个实验室的专业知识。该PI是神经外科助理教授，利用体内电生理学和内在光学成像技术研究啮齿动物癫痫模型中皮质癫痫发作的传播。合作研究者，精神病学助理教授，通过将皮层下胚胎前脑的中间神经元祖细胞移植到出生后皮层，研究了小鼠皮层中间神经元亚型的特征。