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.

项目总结/摘要 超过100万美国人患有颞叶癫痫。不幸的是，其中三分之一的人 无法控制的药物难治性癫痫发作除了降低一个人的生活质量，不受控制的 癫痫发作也大大增加了癫痫猝死的风险。新疗法的发展 覆盖更广泛患者人群的选择将减少患有不受控制的 癫痫发作开发颞叶癫痫新疗法的重要一步是了解 受影响区域的潜在神经回路最常见的颞叶癫痫，癫痫发作的重点是 海马体。目前的项目将探讨如何抑制细胞群与很少事先表征 符合健康和癫痫患者的海马回路。此外，该项目还可以确定一个 候选目标，用于为患有医学疾病的人开发新型有效的治疗方案 难治性颞叶癫痫具体地说，本项目旨在研究在此提及的细胞群， 作为LINCs（或，长距离抑制性神经元一氧化氮合酶（nNOS）表达细胞）。首先，在老鼠体内 慢性颞叶癫痫模型，我将测试LINCs是一个有凝聚力的细胞群的假设 对健康的和癫痫的海马体提供强的、持久的和广泛的抑制。然后， 使用我的顾问以前开发的按需光遗传学癫痫干预策略， 赞助商Krook-Magnuson博士，我将检验LINCs能够缩短癫痫发作持续时间的假设， 频率和严重性。这个项目的结果将增加我们对健康海马电路的了解 并将阐明癫痫患者大脑中的回路是如何改变的。此外，这项研究的结果可能 为开发新的抗癫痫治疗药物确定新的靶点。通过拟议的培训 在这里，我将获得在细胞和回路水平上研究神经系统疾病所必需的工具，并将 做好充分的准备，为独立科学家的职业生涯迈出下一步。