Prevention of Temporal Lobe Epilepsy

描述(申请人提供)：癫痫是一种严重的常见神经疾病，估计困扰着全球1%的人口，而颞叶癫痫(TLE)是成人中最严重和最难治的癫痫。没有有效的预防措施。临床观察和对不同动物模型的研究支持了以下观点：儿童时期的发热性癫痫状态(FSE)可以在以后的生活中导致TLE。因此，FSE相关的TLE是一种可以考虑预防性治疗的癫痫综合征。我们的首要目标是确定(A)FSE后TLE临床预防试验的候选化合物和后备药物，以及(B)应作为目标的高危个体的预测性生物标志物(S) 进行干预。为了实现这些目标，我们组建了一个临床前研究团队，专注于癫痫发生机制的研究。这项计划拨款的目标是：1)创建紧凑的行政基础设施，促进我们的核心团队、NIH与我们的学术和制药公司顾问之间的互动，并吸引更多的研究人员参与其开发的项目；2)进行试验性研究，旨在识别与临床表型一致的动物模型中的生物标记物。我们的意图是提交后续的申请，以建立一个没有疾病修改和预防墙的癫痫中心(CWW)。以下目标将有助于实现CWW规划阶段的目标。目标1建立一个行政结构，监督和协调规划赠款期间的活动，并为建立一个没有围墙的中心做准备。目的2确定一种与延长FSE后的成像生物标志物密切相关的细胞因子生物流体分析谱。目的3建立一个多机构小组，协调研究高温或KA诱导癫痫发作后MRI成像的应用和可预测性。目的4通过对FEBSTAT队列的研究，直接检验这些生物标志物对人类癫痫、晚期海马区损伤和认知障碍的可预测性。

DESCRIPTION (provided by applicant): Epilepsy is a serious common neurological disorder, afflicting an estimated 1% of the population worldwide, and temporal lobe epilepsy (TLE) is the most severe and refractory epilepsy in adults. There is no effective prevention. Clinical observations as well as studies of diverse animal models underlie the idea that febrile status epilepticus (FSE) in childhood can cause TLE later in life. Therefore, FSE-related TLE is one epilepsy syndrome for which preventive therapies could be examined. Our overarching goals are to identify (a) a candidate compound and a backup for a clinical prevention trial of TLE following FSE, and (b) predictive biomarker(s) for individuals at high risk that should be targeted for intervention. To achieve these goals, we have assembled a team of preclinical investigators with research focus on mechanisms of epileptogenesis. The objectives of this planning grant are: 1) To create a compact administrative infrastructure that will promote interactions among our core team, NIH and our academic and pharmaceutical company consultants as well as draw additional investigators into the project it develops; 2) To conduct pilot studies aimed at identification of biomarkers across animal models aligned with the clinical phenotype. Our intent is to submit a subsequent application for an Epilepsy Center without Walls on Disease Modification and Prevention (CWW). The following Aims will enable the objectives of the planning phase of the CWW. Aim 1 to develop an administrative structure that oversees and coordinates the activities during the planning grant and prepares for a Center without Walls. Aim 2 To identify a cytokine bio fluid analyte profile that correlates strongly with imaging biomarkersafter prolonged FSE. Aim 3 to establish a multi-institutional team to coordinate study of the utiliy and predictability of MRI imaging following induction of seizures induced by hyperthermia or KA. Aim 4 to directly examine the predictability of these biomarkers for epilepsy, late hippocampal injury, and cognitive impairments in humans, by studying the FEBSTAT cohort.