Validation of a Novel Mouse Model of Temporal Lobe Epilepsy

颞叶癫痫新型小鼠模型的验证

基本信息

批准号：
10618726
负责人：
EDWARD PEREZ-REYES
金额：
$ 40.67万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618726
关键词：
Address Adoption Affect Animal Model Animals Antiepileptic Agents Antiepileptogenic Appearance Biological Assay Brain region Caricatures Cell Death Cessation of life Clinical Clinical Trials Design Data Development Disease Drug Screening Electric Stimulation Electroconvulsive Shock Electroencephalography Enterobacteria phage P1 Cre recombinase Epilepsy Frequencies Functional disorder Funding Genes Goals Grant Hippocampus (Brain)Human Lead Link Medication Management Medicine Modeling Mouse Strains Mus National Institute of Neurological Disorders and Stroke Neurons Partial Epilepsies Patients Persons Pharmaceutical Preparations Pharmacology Phase Play Problem Solving Protocols documentation Rattus Research Rodent Running Sclerosis Seizures Severities Status Epilepticus Temporal Lobe Epilepsy Testing Tonic - clonic seizures United States National Institutes of Health Universities Utah Validation Virginia Work base cost drug discovery drug testing efficacy testing excitatory neuron experience hippocampal sclerosis human disease improved inhibitory neuron kainate mouse model neuron loss novel novel therapeutics process repeatability programs promoter screening screening program translational goal vesicular GABA transporter

项目摘要

Project summary The long-term goal of these studies is to develop novel therapeutics for epilepsy patients whose seizures are not well-controlled by current drugs (pharmacoresistant). Many of these patients have a type of focal epilepsy called temporal lobe epilepsy (TLE). There has been little progress in the development of novel therapies for these patients because of the lack of suitable animal models. Current TLE models show much greater neuronal death and hippocampal sclerosis than observed in patients, and a highly variable occurrence of seizures that precludes drug testing. The proposed studies will validate the usefulness of new mouse model of TLE that overcomes these problems. It was discovered that a mild kindling protocol of a specific strain of mice, VGAT- Cre, led to spontaneous seizures. Kindling refers to the process where repeated electrical stimulations eventually trigger tonic-clonic seizures. However, kindling only leads to spontaneous seizures in VGAT-Cre mice. These mice express Cre recombinase under the control of the vesicular GABA transporter (VGAT), a gene that is specifically expressed in GABAergic inhibitory neurons. Loss, or dysfunction, of these neurons in the hippocampus has been linked to the development of temporal lobe epilepsy. The first aim of this study will optimize kindling protocols to generate mice with an ideal frequency of spontaneous seizures for drug testing. The second aim is to validate that these mice respond to currently available antiseizure drugs. This work will be done by Dr. Wilcox’s group at the University of Utah, who also directs the NIH-sponsored Epilepsy Therapy Screening Program.

项目概要这些研究的长期目标是为癫痫患者开发新的治疗方法。目前的药物不能很好地控制（耐药），其中许多患者患有局灶性癫痫。称为颞叶癫痫（TLE）的新疗法的开发进展甚微。由于缺乏合适的动物模型，这些患者的神经元数量要大得多。死亡和海马硬化的发生率比在患者中观察到的要高，并且癫痫发作的发生率高度可变排除药物测试。拟议的研究将验证新的 TLE 小鼠模型的有效性。人们发现，一种针对特定品系小鼠的温和点燃方案 VGAT- 克服了这些问题。 Cre，导致自发性癫痫发作是指重复电刺激最终的过程。然而，点燃只会导致 VGAT-Cre 小鼠自发性癫痫发作。小鼠在囊泡 GABA 转运蛋白 (VGAT) 的控制下表达 Cre 重组酶，该基因特异性表达于 GABA 能抑制性神经元中，这些神经元的缺失或功能障碍。海马体与颞叶癫痫的发展有关。这项研究的第一个目的是。优化点燃方案，以产生具有理想自发癫痫发作频率的小鼠，用于药物测试。第二个目标是验证这些小鼠对目前可用的抗癫痫药物的反应。由犹他大学 Wilcox 博士的团队完成，该团队还负责 NIH 赞助的癫痫治疗筛选计划。