Does a Common Mechanism Trigger Attacks in Episodic Ataxia Type 2?

2 型发作性共济失调是否有共同机制引发发作？

基本信息

批准号：
8835728
负责人：
Ariel Vitenzon
金额：
$ 4.27万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-21 至 2017-09-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8835728
关键词：
Action Potentials Adrenergic Agents Adrenergic Receptor Affect Agonist Alcohol consumption Alcohols Animals Ataxia Automobile Driving Behavior Brain Caffeine Calcium Calcium Channel Calmodulin Cells Cerebellum Coupling Data Dyskinetic syndrome Dystonia Emotional Stress Ethanol Exhibits Familial Hemiplegic Migraine Fire - disasters Frequencies Functional disorder Genes Goals In Vitro Intervention Ion Channel Knowledge Lead Link Measures Modeling Molecular Molecular Biology Motor Movement Mus Muscle Mutation Nervous system structure Neurons Norepinephrine Output P-Q type voltage-dependent calcium channel Patients Pattern Pharmaceutical Preparations Phosphorylation Physiological Probability Protein Isoforms Purkinje Cells Q-Type Calcium Channels Quality of life Receptor Activation Rodent Rodent Model Stress Symptoms Techniques Testing Work acute stress adrenergic behavior test calcium-activated potassium channel small-conductance casein kinase II drug development improved in vivo loss of function mutation mouse model nervous system disorder new therapeutic target prevent public health relevance research study response stressor voltage

Action Potentials Adrenergic Agents Adrenergic Receptor Affect Agonist Alcohol consumption Alcohols Animals Ataxia Automobile Driving Behavior Brain Caffeine Calcium Calcium Channel Calmodulin Cells Cerebellum Coupling Data Dyskinetic syndrome Dystonia Emotional Stress Ethanol Exhibits Familial Hemiplegic Migraine Fire - disasters Frequencies Functional disorder Genes Goals In Vitro Intervention Ion Channel Knowledge Lead Link Measures Modeling Molecular Molecular Biology Motor Movement Mus Muscle Mutation Nervous system structure Neurons Norepinephrine Output P-Q type voltage-dependent calcium channel Patients Pattern Pharmaceutical Preparations Phosphorylation Physiological Probability Protein Isoforms Purkinje Cells Q-Type Calcium Channels Quality of life Receptor Activation Rodent Rodent Model Stress Symptoms Techniques Testing Work acute stress adrenergic behavior test calcium-activated potassium channel small-conductance casein kinase II drug development improved in vivo loss of function mutation mouse model nervous system disorder new therapeutic target prevent public health relevance research study response stressor voltage

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项目摘要

DESCRIPTION (provided by applicant): Episodic ataxia type 2 (EA2) is a neurological disorder caused by mutations in the CACNA1A gene encoding for the pore forming α-1a subunit of the P/Q type voltage gated calcium channel (Cav2.1). EA2 patients exhibit episodic attacks of severe ataxia triggered by different stressors such as, caffeine and alcohol consumption and physical or emotional stress. Previous work in our lab has shown that the motor attacks in a rodent EA2 model, tottering, are due to an aberrant output from the cerebellum driven by erratic burst firing of Purkinje cells (PC). The tottering mouse is a well-established rodent model of EA2. They carry a spontaneous mutation in the CACNA1A gene rendering the Cav2.1 channel non-functional and exhibit motor attacks induced by stress, caffeine and alcohol similar to EA2 patients. Interestingly, all three triggers result in the same change in the firing pattern of PCs n these animals, suggesting a common converging mechanism. PCs are intrinsically active and in vivo exhibit tonic firing at 50 spikes per second. This firing pattern is partially governed by the tight coupling of Cav2.1 channels to the small conductance calcium activated potassium channels (SK2) that help regulate the intrinsic activity of these cells. It has been shown that blocking SK2 channels promotes burst firing of wild type PCs, whereas activating them in the cerebellum of tottering mice restores PC regularity and alleviates attacks induced by caffeine or stress. Give that the calcium current through Cav2.1 channels in tottering mice is already diminished and that SK2 channels are gated by Cav2.1 dependent calcium, a further reduction in SK2 activity could be the cause for the observed bursting of PCs during attacks. Indeed, preliminary data from our lab suggests that all three triggers converge on the modulation of SK2 activity. Interestingly, this modulation seems to be dependent on increases in norepinephrine (NE) levels in the cerebellum, a phenomenon known to occur in response to stress, caffeine and alcohol. Thus, our working hypothesis is that all three triggers functionally converge to reduce open probability of PCs SK2 channels via a NE dependent mechanism. My main goal in this proposal is to further delineate the mechanism driving the attacks in tottering mice by perturbing SK2 gating and asking how it will affect attacks. I plan to achieve this by combining electrophysiological techniques together with molecular biology and behavioral tests. This powerful approach will allow me to link molecular mechanisms, physiological function and behavior.

描述（由适用提供）：2型发作性共济失调（EA2）是一种神经系统疾病，是由Cacna1a基因在编码孔形成P/Q型电压门控钙通道的α-1A亚基的突变引起的（CAV2.1）。 EA2患者表现出由不同压力源（例如咖啡因和酒精消耗以及身体或情绪压力）触发的严重共济失调的发作发作。我们实验室中的先前工作表明，啮齿动物EA2模型中的运动攻击tottering是由于purkinje细胞（PC）爆发不稳定的小脑的异常输出所致。摇摇欲坠的小鼠是EA2的啮齿动物模型。他们在CACNA1A基因中携带一个赞助突变，渲染CAV2.1通道由压力，咖啡因和酒精引起的非功能性和暴露的运动攻击，类似于EA2患者。触发器导致PC的发射模式与这些动物的发射模式发生了相同的变化，这表明一种常见的融合机制。 PC是本质上活跃的，体内以每秒50峰值的刺激表现出滋补。这种射击模式部分由 Cav2.1通道与小电导钙激活钾通道（SK2）的紧密偶联有助于调节这些细胞的内在活性。已经表明，阻止SK2通道会促进野生型PC的爆发爆发，而在总体小鼠的小脑中激活它们会恢复PC的规律性，并减轻咖啡因或压力引起的攻击。给出总体小鼠中通过CAV2.1通道的钙电流已经减少，并且SK2通道由CAV2.1依赖性钙门控，SK2活性的进一步降低可能是在攻击过程中观察到的PC爆发的原因。实际上，我们实验室的初步数据表明，这三个触发因素都融合了SK2活性的调制。有趣的是，这种调节似乎取决于小脑中去甲肾上腺素（NE）水平的升高，这是一种已知在应激，咖啡因和酒精响应的现象。这就是我们的工作假设是，所有三个触发器在功能上都会收敛，以通过NE依赖机制降低PCS SK2通道的开放概率。我在该提案中的主要目标是进一步描述通过扰动SK2门口并询问它将如何影响攻击的机制。我计划通过将电生理技术与分子生物学和行为测试结合在一起来实现这一目标。这种强大的方法将使我能够将分子机制，身体功能和行为联系起来。