GABA-A Receptor Function in Pediatric Focal Cortical Dysplasia

描述（由申请人提供）：申请人是一名在临床儿科神经病学和实验神经生理学和神经药理学方面受过训练的内科科学家。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，以便成为儿科癫痫研究领域的独立研究者。尽管在癫痫的药物和手术治疗方面取得了进展，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）的致痫区是难治性癫痫发作的常见来源，然而，生理学和因此，这些区域的最佳管理知之甚少。本研究试图解决FCD中GABA-A受体功能异常是癫痫发病机制和抗癫痫药物治疗反应差的一个因素的假设。这一假设将通过使用最近描述的一种技术进行检验，该技术允许在注射爪蟾卵母细胞后，用从脑标本中分离的细胞膜对其天然配置的人类GABA-A受体进行电生理分析。本建议的具体目标包括：1)建立对爪蟾卵母细胞进行膜注射后儿科对照和FCD手术标本GABA-A受体电流的测量方法，2)分析对照和FCD标本GABA-A受体的内在生理特性，3)比较对照和FCD标本中GABA-A受体电流对抗癫痫药物和内源性调节剂等药物的反应，4)电生理表现与临床病程及抗癫痫药物反应的相关性。这项研究的结果将为GABA-A受体在癫痫中的作用提供更多的见解，并有助于优化FCD引起的顽固性癫痫发作的治疗。该候选人最近在华盛顿大学神经内科和儿童医院及地区医疗中心任职，该中心致力于通过提供充足的保护时间、研究设施和指导，将她发展成为一名独立的研究者。Bruce R. Ransom，医学博士，在中枢神经系统细胞生理学的研究以及医师科学家的指导方面拥有丰富的经验，将作为申请人学术生涯发展的导师。还将成立一个由神经内科既定调查人员组成的咨询委员会，以提供额外指导。

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.