GABA-A Receptor Function in Pediatric Focal Cortical Dysplasia

申请人描述(由申请人提供)：申请人是一名内科科学家，受过临床儿科神经学和实验神经生理学及神经药理学方面的培训。获得导师临床科学家发展奖将使候选人能够巩固她以前的培训，以便成为儿科癫痫研究领域的独立调查员。尽管癫痫的药理学和外科治疗取得了进展，但顽固性癫痫发作仍然是儿童发病率和潜能丧失的重要原因。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，然而，对这些区域的生理学和最佳处理知之甚少。这项建议致力于解决这一假说，即FCD存在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不良的一个因素。这一假设将通过使用最近描述的一项技术来验证，该技术允许在将从大脑标本中分离的细胞膜注射到非洲爪哇卵母细胞后，对处于其原始配置的人GABA-A受体进行电生理学分析。这项建议的具体目的包括：1)建立膜注入非洲爪哇卵母细胞后儿童对照和FCD手术标本GABA-A受体电流的测量方法，2)分析对照和FCD标本中GABA-A受体的内在生理特性，3)比较对照和FCD标本中GABA-A受体电流对药物的反应，包括抗癫痫药物和内源性调节剂，以及4)电生理学结果与临床病程和抗癫痫药物反应的相关性。这项研究的结果将进一步深入了解GABA-A受体在癫痫中的作用，并有助于优化FCD引起的顽固性癫痫的治疗。这位候选人最近在华盛顿大学儿童医院和地区医学中心的神经病学系担任了一个职位，该中心致力于通过提供充足的保护时间、研究设施和指导来发展她作为一名独立研究员的能力。布鲁斯·R·兰瑟姆博士在研究中枢神经系统细胞生理学以及指导内科科学家方面拥有非凡的经验，她将在申请者的学术生涯发展中担任导师。还将组建一个咨询委员会，由神经病学系内的资深调查人员组成，以提供额外的指导。

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.