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：
7587515
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 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587515
关键词：
Action Potentials Age Ankyrins Axon Behavioral Biological Biological Models Brain Cell Line Cells Cultured Cells Dependence Development Disease Employee Strikes Epilepsy Exhibits Familial benign neonatal epilepsy Frequencies Genes Goals Hippocampus (Brain)Human Inborn Genetic Diseases Inherited Interneurons Ion Channel Lead Life 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 Scaffolding Protein Seizures Severities Signal Pathway Signal Transduction Site Syndrome System Testing Tetanus Helper Peptide Therapeutic Time 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）：仔细研究负责罕见的孟德尔形式的人类神经疾病的基因是一种有力的方法，可以深入了解共同疾病的原因，治疗和潜在治疗。最近发现了神经元KCNQ基因，这是由于寻找引起良性家族性新生儿抽搐的突变基因，这是一种常染色体显性癫痫综合征，与婴儿期和整个生命中的癫痫发作有关。神经元KCNQ基因的突变也会导致肌科（一种周围神经障碍）和耳聋。 KCNQ基因编码电压依赖性钾通道的亚基。拟议工作的长期目标是了解这些神经元KCNQ通道的体内功能，以更好地理解基本的大脑信号传导机制并利用这些机制来用于神经系统疗法。 KCNQ通道通过在大脑的特定位置以及它们作为神经递质受体和细胞内信号通路的效应子的能力来调节神经元兴奋性。专门确定KCNQ通道位于脑回路中的位置，以及受体，途径和相互作用的蛋白如何调节其在大脑中的活性，将增强我们在涉及过度兴奋性或过度兴奋性或不平衡性神经传递中的变化和不平衡的状态下，将这些通道作为治疗靶标的能力增强，例如调节性神经传递。当前的提案重点介绍了海马轴突上的KCNQ通道，研究者和其他人的先前工作表明KCNQ通道起着重要作用。它利用新近可用的突变小鼠具有KCNQ2突变以及增加的癫痫敏感性和自发癫痫发作的表型。具体目的是：（1）在正常和突变啮齿动物的发育和成熟大脑中绘制KCNQ亚基的定位；（2）将靶向KCNQ亚基的机制定义为Ranvier的轴突初始段和节点；（3）分析亚细胞和细胞水平上轴突KCNQ通道的功能。