Validation of a novel mouse model of temporal lobe epilepsy

新型颞叶癫痫小鼠模型的验证

基本信息

批准号：
9810436
负责人：
EDWARD PEREZ-REYES
金额：
$ 36.34万
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 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9810436
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 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 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.

项目摘要这些研究的长期目标是为癫痫发作的癫痫患者开发新的治疗目前的药物（药剂敏感）无法控制。这些患者中的许多患有局灶性癫痫称为临时叶癫痫（TLE）。在开发新疗法方面几乎没有进步这些患者由于缺乏合适的动物模型。当前的TLE模型显示出更大的神经元与患者中观察到的死亡和海马硬化症相比，癫痫发作高度可变。排除药物测试。拟议的研究将验证新的小鼠模型的有用性克服了这些问题。已经发现，特定小鼠特异性菌株的轻度点燃方案VGAT- CRE，导致赞助癫痫发作。点燃是指最终重复电刺激的过程触发强调持续性癫痫发作。然而，点燃只会导致VGAT-CRE小鼠的自发癫痫发作。这些小鼠在囊泡GABA转运蛋白（VGAT）的控制下表达CRE重组酶，这是一种基因这些神经元中这些神经元的损失或功能障碍海马与临时叶癫痫的发展有关。这项研究的第一个目的将优化点燃方案以生成具有理想的赞助癫痫发作频率进行药物测试的小鼠。第二个目的是验证这些小鼠对当前可用的抗性药物的反应。这项工作将是由犹他大学威尔科克斯博士小组完成，他还指导NIH赞助的癫痫疗法筛选计划。