Mechanisms of benign neonatal familial convulsions

良性新生儿家族性惊厥的机制

基本信息

批准号：
7194363
负责人：
EDWARD C COOPER
金额：
$ 34.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7194363
关键词：
Action Potentials Age Ankyrins Axon Behavioral Biological Biological Models Brain Cell Line Cells Condition Cultured Cells Dependence Development Disease Disruption Employee Strikes Epilepsy Exhibits Familial benign neonatal epilepsy Frequencies Genes Goals Hippocampus (Brain)Human Inborn Genetic Diseases Inherited Interneurons Ion Channel Lead Life Localized Location Maps Mediating Methods Missense Mutation Molecular Mus Mutant Strains Mice Mutation Myokymia Neonatal Neurologic Neurons Neurotransmitter Receptor Pain Pathway interactions Peripheral Peripheral Nerves Phenotype Physiological Play Potassium Channel Predisposition Presynaptic Terminals Proteins Ranvier&apos s Nodes Relative (related person)Research Personnel Risk Rodent Role Role playing therapy Scaffolding Protein Seizures Severities Signal Pathway Signal Transduction Site Syndrome System Testing Tetanus Helper Peptide Therapeutic Time Week Work deafness density design in vivo infancy insight mutant nervous system disorder neuron loss neuronal cell body neuronal excitability neurotransmission novel postnatal prevent programs protein protein interaction receptor research study septohippocampal therapeutic target tool voltage

项目摘要

DESCRIPTION (provided by applicant): Careful study of genes responsible for rare mendelian forms of human neurological disorders is a powerful approach for gaining insight into the causes, treatment, and potential cure for common, related diseases. The neuronal KCNQ genes were recently discovered as the result of the search for mutant genes causing Benign Familial Neonatal Convulsions, an autosomal dominant epileptic syndrome associated with seizures in infancy and throughout life. Mutations in neuronal KCNQ genes also result in myokymia (a peripheral nerve disorder) and deafness. The KCNQ genes encode subunits of voltage-dependent potassium channels. The long term goals of the proposed work is to understand the in vivo functions of these neuronal KCNQ channels, in order to better understand basic brain signaling mechanisms and to exploit these mechanisms for neurological therapeutics. KCNQ channels regulate neuronal excitability through their intrinsic, voltage-gated activity at particular locations in brain, and through their ability to serve as effectors for neurotransmitter receptors and intracellular signaling pathways. Determining specifically where KCNQ channels are localized in brain circuits, and how receptors, pathways and interacting proteins modulate their activity in the brain, will enhance our ability to exploit these channels as therapeutic targets in conditions involving excessive excitability or alterations and imbalances in modulatory neurotransmission, such as epilepsy and pain syndromes. The current proposal focuses on KCNQ channels on axons in hippocampus, where previous work by the investigator and others indicates KCNQ channels play important roles. It exploits newly available mutant mice with KCNQ2 mutations and phenotypes of increased seizure susceptibility and spontaneous seizures. The specific aims are to: (1) map the localization of KCNQ subunits in mammalian septohippocampal networks in developing and mature brain of normal and mutant rodents; (2) define the mechanisms targeting KCNQ subunits to axon initial segments and nodes of Ranvier; and (3) analyze the function of axonal KCNQ channels at the subcellular and cellular level.

描述（由申请人提供）：仔细研究导致罕见孟德尔形式人类神经系统疾病的基因是深入了解常见相关疾病的原因、治疗和潜在治愈方法的有效方法。最近在寻找导致良性家族性新生儿惊厥的突变基因时发现了神经元 KCNQ 基因，良性家族性新生儿惊厥是一种与婴儿期和终生癫痫发作相关的常染色体显性癫痫综合征。神经元 KCNQ 基因突变还会导致肌颤（一种周围神经疾病）和耳聋。 KCNQ 基因编码电压依赖性钾通道亚基。这项工作的长期目标是了解这些神经元 KCNQ 通道的体内功能，以便更好地了解基本的大脑信号传导机制并利用这些机制进行神经治疗。 KCNQ 通道通过其在大脑特定位置的内在电压门控活动以及作为神经递质受体和细胞内信号通路效应器的能力来调节神经元兴奋性。具体确定 KCNQ 通道在大脑回路中的定位，以及受体、通路和相互作用蛋白如何调节其在大脑中的活动，将增强我们在涉及过度兴奋或调节性神经传递改变和不平衡的情况下利用这些通道作为治疗靶点的能力，例如癫痫和疼痛综合症。目前的提案重点关注海马轴突上的 KCNQ 通道，研究者和其他人之前的工作表明 KCNQ 通道发挥着重要作用。它利用了新近出现的具有 KCNQ2 突变和癫痫易感性增加和自发性癫痫发作表型的突变小鼠。具体目标是：（1）绘制正常和突变啮齿动物发育和成熟大脑中KCNQ亚基在哺乳动物隔膜海马网络中的定位； (2)定义KCNQ亚基针对Ranvier轴突初始段和节点的机制； (3)在亚细胞和细胞水平上分析轴突KCNQ通道的功能。