Impaired KCC2 function underlies pharmacoresistant seizures

KCC2 功能受损是耐药性癫痫发作的原因

基本信息

批准号：
8494931
负责人：
Stephen J Moss
金额：
$ 24.75万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494931
关键词：
Address Adult Alanine Animal Model Animals Anti-Anxiety Agents Anticonvulsants Antiepileptic Agents Asses Benzodiazepines Biochemical Biological Assay Brain Development Disease Drug Targeting Drug resistance Epilepsy Family Foundations Genetic Hippocampus (Brain)Homeostasis Human In Vitro Knock-in Mouse Lead Life Mediating Medicine Modeling Mutant Strains Mice Mutation Neuraxis Neurologic Neurons Neurotransmitter Receptor Patients Pharmaceutical Preparations Pharmacotherapy Phosphorylation Physicians Process Property Proteins Quality of life Refractory Research Resistance Resistance development Role Seizures Serine Signal Transduction Slice Spinal Cord Status Epilepticus Surface Synapses Techniques Temporal Lobe Epilepsy Testing Therapeutic Time Treatment Efficacy Work brain cell brain tissue cost gamma-Aminobutyric Acid hypnotic improved kainate loss of function molecular array molecular scale nervous system disorder novel therapeutics protein K public health relevance receptor research study response symporter therapeutic effectiveness transmission process

项目摘要

DESCRIPTION (provided by applicant): Epilepsy is a curable disease, but nearly one out of four patients develops seizures that are resistant to anti- epileptic medications. Seizures are neurological conditions characterized by abnormal brain waves and decreased inhibition. The fundamental determinant of inhibition in the brain is the protein KCC2, which dictates how key anti-epileptic drug targets work. Without KCC2 these targets would no longer function properly, and consequently, neither would the first- and second-line anti-epileptic drug therapies. KCC2 was only recently found to be severely diminished in the brains of people suffering from drug-resistant epilepsy. This proposal represents the first attempt to unequivocally identify the loss o this protein as the common feature of drug- resistant seizures. Given the fundamental role of this protein, it is vital that the proposed experiments are completed for the benefit of people suffering from this as yet incurable disorder. The project will consist of an array of molecular, electrophysiological, and genetic experiments to confirm the hypothesized role of KCC2 in animal models of drug-resistant seizures. The first project aim utilizes a new strategy to examine impaired KCC2 function on the molecular scale. This will demonstrate that a deficit in KCC2 function impedes inhibitory signaling between brain cells. The second project aim utilizes a model of drug-resistant seizures in animal brain tissue to directly demonstrate that the deficit in KCC2 function causes this disorder. This will be the first demonstration of this process in any model of drug-resistant seizures. The final project aim will directly address a longstanding unanswered question in medicine. Physicians have known for years that drug-resistant seizures develop with time, slowly and sometimes rapidly evolving from a state that can be treated into one that cannot. These experiments will be the first demonstration in a living animal brain that the progressive loss of KCC2 function underlies the development of these drug-resistant seizures. Such a finding would suggest that rescuing KCC2 function could restore the therapeutic effectiveness of current anti-epileptic drugs. The overarching research objective is to lay the foundation for immediate testing of a novel therapeutic strategy that targets KCC2 function to improve the quality of life of those suffering from drug-resistant seizures.

描述（由申请人提供）：癫痫是一种可治愈的疾病，但四分之一的患者中有几乎有一个癫痫发作对抗癫痫药的抗性。癫痫发作是神经系统疾病，其特征是异常的脑波和抑制作用降低。大脑抑制作用的基本决定因素是蛋白质KCC2，它决定了关键的抗癫痫药靶标。没有KCC2，这些靶标将不再正常运行，因此，一线和二线抗杀菌药物疗法也不会。直到最近发现，KCC2在患有耐药性癫痫的人群的大脑中被严重减少。该提议是明确识别该蛋白质损失的首次尝试，这是抗药性癫痫发作的共同特征。鉴于该蛋白质的基本作用，至关重要的是，提出的实验是为了使患者尚无法治愈的疾病的受益而完成。该项目将由一系列分子，电生理和遗传实验组成，以确认KCC2在耐药性癫痫的动物模型中的假设作用。第一个项目的目标利用新策略来检查分子量表的KCC2功能受损。这将表明KCC2功能的缺陷阻碍了脑细胞之间的抑制信号传导。第二个项目的目的是利用动物脑组织中耐药性癫痫发作的模型直接证明KCC2功能的不足会导致这种疾病。在任何耐药性癫痫发作模型中，这都是该过程的首次演示。最终的项目目标将直接解决医学上长期未解决的问题。多年来，医师知道耐药性癫痫发作随着时间的流逝而发展，缓慢地，有时从一个可以将其视为无法处理的状态中迅速发展。这些实验将是活动物大脑中的第一次演示，即KCC2功能的逐渐丧失是这些耐药性癫痫发作的发展。这样的发现表明，拯救KCC2功能可以恢复当前抗癫痫药的治疗有效性。总体研究目标是立即测试一种针对KCC2功能的新型治疗策略的基础，以改善耐药性癫痫发作的人的生活质量。