Mechanisms of benign neonatal familial convulsions

良性新生儿家族性惊厥的机制

• 批准号: 7544878
• 负责人: EDWARD C COOPER
• 金额: $ 2.36万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/7544878
• 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' 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

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.

仔细研究导致人类神经系统疾病的罕见孟德尔形式的基因是一个强大的工具 深入了解常见相关疾病的原因、治疗和潜在治愈方法。这 神经元 KCNQ 基因是最近在寻找导致良性肿瘤的突变基因时发现的。 家族性新生儿惊厥，一种与癫痫发作相关的常染色体显性癫痫综合征 婴儿期和终生。神经元 KCNQ 基因突变也会导致肌颤（周围神经 障碍）和耳聋。 KCNQ 基因编码电压依赖性钾通道亚基 拟议工作的长期目标是了解这些神经元 KCNQ 的体内功能 通道，以便更好地理解基本的大脑信号传导机制并利用这些机制 神经治疗学。 KCNQ 通道通过其内在的电压门控活动调节神经元兴奋性 大脑中的特定位置，并通过它们作为神经递质受体效应器的能力 细胞内信号通路。确定 KCNQ 通道在大脑中的具体定位位置 电路，以及受体、通路和相互作用的蛋白质如何调节它们在大脑中的活动，将 增强我们在涉及过度治疗的情况下利用这些通道作为治疗靶点的能力 调节性神经传递的兴奋性或改变和不平衡，例如癫痫和疼痛 综合症。当前的提案重点关注海马体轴突上的 KCNQ 通道，之前的提案 研究人员和其他人的工作表明 KCNQ 渠道发挥着重要作用。它新开发了 具有 KCNQ2 突变和癫痫易感性增加表型的可用突变小鼠 自发性癫痫发作。 具体目标是：（1）绘制哺乳动物中KCNQ亚基的定位图 正常和突变啮齿动物发育和成熟大脑中的隔海马网络； (2) 定义 将 KCNQ 亚基靶向 Ranvier 轴突初始段和节点的机制； (3) 分析 轴突 KCNQ 通道在亚细胞和细胞水平的功能。