GABA-A Receptor Function in Pediatric Focal Cortical Dysplasia

GABA-A 受体在小儿局灶性皮质发育不良中的功能

• 批准号: 6961253
• 负责人: LAURA A JANSEN
• 金额: $ 16.83万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6961253
• 关键词: GABA receptor; Xenopus oocyte; anticonvulsants; brain electrical activity; clinical research; electrophysiology; epilepsy; human subject; patient oriented research; pediatrics; protein structure function

DESCRIPTION (provided by applicant): The applicant is a physician-scientist trained in clinical pediatric neurology and experimental neurophysiology and neuropharmacology. Receipt of the Mentored Clinical Scientist Development Award would allow the candidate to consolidate her previous training in order to become an independent investigator in the field of pediatric epilepsy research. Despite advances in the pharmacologic and surgical treatment of epilepsy, intractable seizures remain a substantial cause of morbidity and loss of potential in children. Epileptogenic areas of focal cortical dysplasia (FCD) are a common source of intractable seizures, yet the physiology and, therefore, the optimal management of these regions is poorly understood. This proposal endeavors to address the hypothesis that abnormal GABA-A receptor function is present in FCD, and is a factor in the pathogenesis of epilepsy and poor response to antiepileptic drug treatment. This hypothesis will be tested through the use of a recently described technique allowing electrophysiologic analysis of human GABA-A receptors in their native configuration after injection of Xenopus oocytes with cellular membranes isolated from brain specimens. The Specific Aims of this proposal include: 1) Establishment of methods for measurement of GABA-A receptor currents from pediatric control and FCD surgical specimens after membrane injection into Xenopus oocytes, 2) analysis of intrinsic physiologic properties of GABA-A receptors in control and FCD specimens, 3) comparison of the responses of GABA-A receptor currents to pharmacologic agents, including antiepileptic drugs and endogenous modulators, in control and FCD specimens, and 4) correlation of electrophysiologic findings with clinical course and response to antiepileptic drugs. The results of this study will provide additional insight into the role of GABA-A receptors in epilepsy and assist in optimization of the treatment of intractable seizures due to FCD. The candidate has recently assumed a position with the Department of Neurology at the University of Washington and Children's Hospital and Regional Medical Center, which is committed to her development as an independent investigator through the provision of ample protected time, research facilities, and instruction. Bruce R. Ransom, MD PhD, who has exceptional experience in the study of central nervous system cellular physiology as well as in the supervision of physician scientists, will serve as the applicant's mentor in the development of her academic career. An Advisory Committee consisting of established investigators within the Department of Neurology will also be assembled to provide additional guidance.

描述（由申请人提供）：申请人是一名接受过临床儿科神经病学、实验神经生理学和神经药理学培训的医生-科学家。获得指导临床科学家发展奖将使候选人巩固她以前的培训，以成为儿科癫痫研究领域的独立研究者。尽管癫痫的药物和手术治疗取得了进展，但顽固性癫痫发作仍然是儿童发病和丧失潜力的重要原因。局灶性皮质发育不良（FCD）的致痫区域是难治性癫痫发作的常见来源，但对这些区域的生理学和最佳管理知之甚少。该提案致力于解决FCD中存在异常GABA-A受体功能的假设，并且是癫痫发病机制和对抗癫痫药物治疗反应不良的因素。这一假设将通过使用最近描述的技术进行测试，允许电生理分析的人GABA-A受体在其天然配置后，注射非洲爪蟾卵母细胞与细胞膜分离的大脑标本。该提案的具体目标包括：1）在膜注射到非洲爪蟾卵母细胞中后，建立用于测量来自儿科对照和FCD手术样本的GABA-A受体电流的方法，2）分析对照和FCD样本中GABA-A受体的内在生理特性，3）比较GABA-A受体电流对药理学试剂（包括抗癫痫药物和内源性调节剂）的响应，在对照和FCD标本中，以及4）电生理结果与临床病程和抗癫痫药物反应的相关性。这项研究的结果将提供额外的见解GABA-A受体在癫痫中的作用，并协助优化治疗顽固性癫痫发作由于FCD。该候选人最近在华盛顿大学神经病学系和儿童医院及区域医疗中心任职，该中心致力于通过提供充足的受保护时间、研究设施和指导，将其发展为独立调查员。布鲁斯河Ransom，MD PhD，在中枢神经系统细胞生理学研究以及医生科学家的监督方面拥有卓越的经验，将担任申请人学术生涯发展的导师。还将组建一个由神经内科既定研究人员组成的咨询委员会，以提供额外的指导。