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

基本信息

批准号：
7254703
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
项目类别：
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/7254703
关键词：
Address Advisory Committees Age Antiepileptic Agents Area Barbiturates Benzodiazepines Bicuculline Brain Brain Neoplasms Brain region Cell physiology Cellular Membrane Characteristics Child Childhood Chloride Channels Clinical Clinical Treatment Collaborations Commit Condition Cortical Dysplasia Databases Dependence Development Doctor of Philosophy Dose Electrodes Epilepsy Epileptogenesis Excision Frequencies GABA-A Receptor Gated Ion Channel Hippocampus (Brain)Human Injection of therapeutic agent Instruction Intractable Epilepsy Investigation Ligands Measurement Medical center Medication Management Membrane Mentored Clinical Scientist Development Award (K08)Mentors Methods Modeling Morbidity - disease rate Neuraxis Neurology Neuropharmacology Numbers Operative Surgical Procedures Pathogenesis Pathologic Patients Pediatric Hospitals Pediatric Neurology Pharmaceutical Preparations Pharmacological Treatment Physicians Physiological Physiology Picrotoxin Positioning Attribute Predisposition Preparation Property Protocols documentation Rate Rattus Refractory Reporting Research Research Personnel Role Scientist Seizures Signal Transduction Site Source Specimen Standards of Weights and Measures Supervision Syndrome System Techniques Testing Time Tissues Training Universities Variant Washington Xenopus oocyte Zinc barbituric acid salt career experience gamma-Aminobutyric Acid insight member neurophysiology neurosurgery novel programs receptor receptor function research facility response sex topiramate voltage voltage clamp

项目摘要

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）：申请人是一位接受过临床儿科神经学、实验神经生理学和神经药理学培训的医师科学家。获得指导临床科学家发展奖将使候选人能够巩固之前的培训，成为小儿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潜力丧失的主要原因。局灶性皮质发育不良（FCD）的致癫痫区域是难治性癫痫发作的常见来源，但人们对这些区域的生理学以及因此的最佳治疗知之甚少。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抗癫痫药物治疗反应不佳的一个因素。这一假设将通过使用最近描述的技术进行测试，该技术允许在注射带有从脑样本中分离的细胞膜的非洲爪蟾卵母细胞后，对天然配置的人类 GABA-A 受体进行电生理分析。该提案的具体目标包括：1) 建立在膜注射到非洲爪蟾卵母细胞后测量儿科对照和 FCD 手术标本中 GABA-A 受体电流的方法，2) 分析对照和 FCD 中 GABA-A 受体的内在生理特性。 FCD 样本，3) 对照和 FCD 样本中 GABA-A 受体电流对药物（包括抗癫痫药物和内源性调节剂）的反应的比较，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。这项研究的结果将为 GABA-A 受体在癫痫中的作用提供更多见解，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、儿童医院和地区医疗中心的神经内科就职，该中心致力于通过提供充足的受保护时间、研究设施和指导来帮助她发展成为一名独立研究者。 Bruce R. Ransom 博士在中枢神经系统细胞生理学研究以及医学科学家的监督方面拥有丰富的经验，他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现有研究人员组成的咨询委员会，以提供额外的指导。