A novel target for seizure suppression in chronic temporal lobe epilepsy

慢性颞叶癫痫发作抑制的新靶点

• 批准号: 9609226
• 负责人: Zoé Christenson Wick
• 金额: $ 2.98万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-31 至 2019-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9609226
• 关键词: Adult; Adverse effects; Affect; American; Attenuated; Brain; Brain Diseases; Cells; Cessation of life; Chronic; Communication; Data; Data Analyses; Data Collection; Detection; Development; Diagnosis; Electroencephalogram; Electrophysiology (science); Epilepsy; Event; Experimental Designs; Fellowship; Foundations; Frequencies; Hippocampus (Brain); Immunohistochemistry; Individual; Intervention; Knowledge; Label; Light; Literature; Measures; Mediating; Medical; Monitor; Morphology; Mus; Names; Neurologic; Neurons; Nitric Oxide Synthase Type I; Operative Surgical Procedures; Opsin; Pathologic; Patients; Pharmaceutical Preparations; Population; Property; Pyramidal Cells; Quality of life; Refractory; Research; Risk; Role; Scientist; Seizures; Severities; Slice; Statistical Data Interpretation; Sudden Death; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Therapeutic; Tissues; Training; Viral; Viral Vector; axonal sprouting; base; biocytin; brain tissue; career; cell type; cohesion; experience; experimental study; genetic approach; in vivo; inhibitory neuron; intersectionality; kainate; mouse model; nervous system disorder; neural circuit; novel; optogenetics; patch clamp; patient population; postsynaptic; receptor; tissue processing; tool

Project Summary/Abstract Over 1 million Americans suffer from temporal lobe epilepsy. Unfortunately, one third of those individuals suffer from uncontrolled, medically refractory, seizures. In addition to diminishing one’s quality of life, uncontrolled seizures also greatly increase the risk of sudden death from epilepsy. The development of new treatment options that reach a wider patient population will reduce the number of people suffering from uncontrolled seizures. An important step in developing new treatments for temporal lobe epilepsy is to understand the underlying neural circuitry of the effected region. Most often in temporal lobe epilepsy, the seizure focus is the hippocampus. The current project will explore how an inhibitory cell population with little prior characterization in the literature fits into the healthy and epileptic hippocampal circuitry. Furthermore, this project may identify a candidate target for the development of novel and efficacious treatment options for people with medically refractory temporal lobe epilepsy. Specifically, this project aims to examine a cell population hereby referred to as LINCs (or, long-range inhibitory neuronal nitric oxide synthase (nNOS)-expressing cells). First, in a mouse model of chronic temporal lobe epilepsy, I will test the hypothesis that LINCs are a cohesive cell population that provide strong, long-lasting, and widespread inhibition to the healthy and epileptic hippocampus. Then, using an on-demand optogenetic seizure intervention strategy previously developed by my advisor and sponsor Dr. Krook-Magnuson, I will test the hypothesis that LINCs are capable of reducing seizure duration, frequency, and severity. The results of this project will increase our knowledge of healthy hippocampal circuitry and will illustrate how that circuitry is altered in the epileptic brain. Additionally, the results of this study may identify a novel target for the development of new anti-seizure therapeutics. Through the training proposed here, I will gain the tools necessary to investigate neurological disorders at a cellular and circuit level and will be well-prepared to take the next steps towards a career as an independent scientist.

项目摘要/摘要 超过100万美国人患有暂时的叶癫痫。不幸的是，这些人中有三分之一 来自未受控制的医学难治性，癫痫发作。除了降低生活质量之外，无法控制 癫痫发作也大大增加了癫痫猝死的风险。新疗法的发展 到达更广泛的患者群体的选择将减少不受控制的人数 癫痫发作。开发临时叶癫痫的新疗法的重要步骤是了解 受影响区域的基础神经回路。大多数通常在临时叶癫痫中，癫痫发作的重点是 海马。当前项目将探讨几乎没有先前表征的抑制细胞群 在文献中，适合健康和癫痫的海马电路。此外，该项目可能会确定 候选目标是为患有医学的人开发新颖有效的治疗选择 难治性临时叶癫痫。具体而言，该项目旨在检查一个细胞人群。 如lincs（或远程抑制性神经元氧化物合酶（NNOS）表达细胞）。首先，在鼠标中 慢性临时叶癫痫的模型，我将测试以下假设：lincs是粘性细胞种群 这为健康和癫痫的海马提供了强烈，持久和广泛的抑制作用。然后， 使用我的顾问和 赞助商Krook-Magnuson博士，我将检验以下假设：Lincs能够减少癫痫发作持续时间， 频率和严重性。该项目的结果将增加我们对健康海马电路的了解 并将说明该电路在癫痫大脑中的改变。此外，这项研究的结果可能 确定新的抗塞氏疗法的新目标。通过提议的培训 在这里，我将获得在细胞和电路水平上研究神经系统疾病所需的工具，并将 准备好迈出独立科学家的职业生涯的下一步。