Cerebellar Function in Health and Disease

健康和疾病中的小脑功能

基本信息

批准号：
8439125
负责人：
Kamran Khodakhah
金额：
$ 47.7万
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：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8439125
关键词：
Alcohols Animal Model Animals Appearance Ataxia Behavior assessment Brain Caffeine Calcium Cells Cerebellar Nuclei Couples Disease Dose Dyskinetic syndrome Emotional Emotional Stress Ethanol Functional disorder Funding Grant Health Hour In Vitro Ingestion Inherited Spinocerebellar Degenerations Learning Light Mediating Migraine Motor Mus Mutation Nervous system structure Neurologic Neurologic Dysfunctions Neurons Neurotransmitters Norepinephrine Normalcy Output Paralysed Paroxysmal Dyskinesias Pathway interactions Patients Phenotype Phosphorylation Physiological Preparation Probability Purkinje Cells Q-Type Calcium Channels Signal Pathway Slice Stimulus Stress Symptoms Techniques Testing Therapeutic Therapeutic Intervention Time Work adrenergic block awake in vivo insight interest mouse model nervous system disorder prevent research study stressor

项目摘要

DESCRIPTION (provided by applicant): A number of neurologic disorders are episodic. The subjects suffering from these disorders have relatively few symptoms in between episodes. Yet they sporadically suffer from severe neurologic attacks which last from minutes to hours. These disorders include migraine, episodic ataxia, and paroxysmal dyskinesia. The episodes are often triggered by factors such as emotional or physical stress, or by ingestion of relatively harmless doses of caffeine and ethanol. Episodic ataxia type 2 (EA2), a hereditary ataxia caused by mutations in the P/Q-type calcium channels, is one such disorder. During the past funding period we provided good evidence in support of the hypothesis that the baseline ataxia seen in EA2 is likely caused by the loss of precision of pacemaking in cerebellar Purkinje cells. We were also able to offer a number of rational pharmacologic therapeutic approaches to restore the precision of pacemaking and lessen ataxia. In this proposal we seek to invest our efforts in unraveling the mechanisms that contribute to episodes of severe ataxia and dyskinesia in EA2. Using well established mouse models of EA2 we wish to test the hypothesis that all three triggers (stress, caffeine and ethanol) cause attacks by converging onto Purkinje cells and transforming their regular activity to highly erratic burst firing. Our working hypothesis is that his transformation is mediated by norepinephrine which increases CK2 dependent phosphorylation of Purkinje cell SK channels. Once phosphorylated, the SK conductance is reduced thereby promoting Purkinje cell burst firing. We will test our working hypothesis using a combination of techniques including behavioral assessment of motor (dys)function, and single cell recordings in acutely dissociated neurons, the brain slice preparation, and in vivo in awake animals. PUBLIC HEALTH RELEVANCE: A number of neurologic disorders are episodic. The subjects suffering from these disorders have relatively few symptoms in between episodes. Yet they sporadically suffer from severe neurologic attacks which last from minutes to hours. These disorders include migraine, episodic ataxia, and paroxysmal dyskinesia. The episodes are often triggered by factors such as emotional or physical stress, or by ingestion of relatively harmless doses of caffeine and ethanol. Episodic ataxia type 2 (EA2), the most common episodic hereditary ataxia, is one such disorder. In this proposal we seek to delineate the mechanism and signaling pathways that mediate the episodic attacks of ataxia and dyskinesia in EA2.

描述（由申请人提供）：许多神经系统疾病是情节性的。在情节之间，患有这些疾病的受试者的症状相对较少。然而，他们偶尔会遭受严重的神经系统攻击，持续时间为几分钟。这些疾病包括偏头痛，发作性共济失调和阵发性发育不全。这些发作通常是由情绪或身体压力等因素引起的，或摄入相对无害的咖啡因和乙醇。一种这种疾病是一种疾病，是由P/Q-Type钙通道中突变引起的，这是一种由P/Q-Type钙通道中突变引起的遗传性共济失调的造影性共济失调（EA2）。在过去的资金期间，我们提供了良好的证据，以支持以下假设：EA2中看到的基线共济失调可能是由于小脑Purkinje细胞中的起搏精度丧失而引起的。我们还能够提供多种理性的药理学治疗方法来恢复起搏的精度和减少共济失调。在这项提案中，我们试图将精力投入到揭开EA2中严重共济失调和运动障碍发作的机制上。使用良好的EA2小鼠模型，我们希望检验以下假设：所有三个触发因素（应力，咖啡因和乙醇）通过收敛到Purkinje细胞并将其常规活动转化为高度不稳定的爆发射击来引起攻击。我们的工作假设是，他的转化是由去甲肾上腺素介导的，该肾上腺素增加了Purkinje细胞SK通道的CK2依赖性磷酸化。一旦磷酸化，SK电导就会降低，从而促进Purkinje细胞爆发。我们将使用包括运动（DYS）函数的行为评估（DYS）和急性解离神经元的单细胞记录，脑切片制剂和在醒着动物中的体内进行测试假设。公共卫生相关性：许多神经系统疾病是情节性的。在情节之间，患有这些疾病的受试者的症状相对较少。然而，他们偶尔会遭受严重的神经系统攻击，持续时间为几分钟。这些疾病包括偏头痛，发作性共济失调和阵发性发育不全。这些发作通常是由情绪或身体压力等因素引起的，或摄入相对无害的咖啡因和乙醇。最常见的情节性遗传性共济失调2型发作性共济失调（EA2）就是一种这样的疾病。在此提案中，我们试图描述EA2中共济失调和运动障碍的发作性发作的机制和信号通路。