Principles of Therapy in Cerebellar Disease: Explorations in Ion Channel Mutants

小脑疾病的治疗原则：离子通道突变体的探索

基本信息

批准号：
8391125
负责人：
JOHN SAMUEL STAHL
金额：
--
依托单位：
LOUIS STOKES CLEVELAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8391125
关键词：
4-Aminopyridine Affect Alcohols Aminopyridines Animals Anterior Area Ataxia Baclofen Bathing Behavior Behavioral Biophysics Blurred vision Brain Calcium Channel Cerebellar Ataxia Cerebellar Diseases Cerebellar vermis structure Cerebellum Characteristics Chemicals Chronic Clinical Data Defect Development Disease Drug usage Dyskinetic syndrome Educational process of instructing Electrophysiology (science)Employee Strikes Engineering Equilibrium Etiology Excision Exhibits Experimental Models Eye Eye Movements Fire - disasters Freedom Functional disorder Gene Mutation Genes Genetic Goals Head High Prevalence Homologous Gene Human Hyperactive behavior In Vitro Inborn Genetic Diseases Inflammatory Inherited Injection of therapeutic agent Injury Investigation Ion Channel Knowledge Lead Left Life Limb Ataxia Link Membrane Military Personnel Motor Mouse Strains Movement Multiple Sclerosis Mus Mutant Strains Mice Mutation Neurologist Neurons P-Q type voltage-dependent calcium channel Pathologic Nystagmus Patients Pattern Periodicity Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Physical therapy Physiological Physiology Population Positioning Attribute Potassium Channel Prevalence Procedures Process Publishing Purkinje Cells Reflex action Research Resistance Sampling Biases Services Signal Transduction Slice Source Specific qualifier value Stress Stroke Structure Symptoms Testing Therapeutic Therapeutic Effect Traumatic Brain Injury Veterans Vision Visual impairment Work behavior observation cell motility disability drug development improved in vivo motor control mouse model mutant neurophysiology oculomotor operation public health relevance research study response theories therapy development tool tumor vestibulo-ocular reflex young adult

项目摘要

DESCRIPTION (provided by applicant): Today's neurologists have few therapies to offer patients suffering the limb ataxia, imbalance, and visual impairment resulting from diseases of the cerebellum. Such patients are common in the veteran population and becoming more so due to traumatic brain injuries suffered in recent military operations. Recent developments, however, suggest that highly effective drugs can be developed: Two drugs that influence neuronal potassium channels have been shown to ameliorate cerebellar deficits in humans and mice, and may provide starting points to develop more efficacious and tolerable drugs. However, the sources of their therapeutic effects are debatable. Likewise, a new theory that ataxia can originate in disturbed rhythmicity of cerebellar Purkinje cells suggests procedures for drug development, but the theory is controversial and requires more investigation. This project will lay a better groundwork for drug development by clarifying the origins of cerebellar motor dysfunction and mechanism of one existing treatment. We focus on ocular motility abnormalities in mice carrying mutations of the CACNA1A gene of the P/Q (CaV2.1) calcium channel, but the results should be applicable to other causes and manifestations of cerebellar dysfunction. Specific Aim 1 involves eye movement recordings in the CACNA1A mutant tottering, and in normal mice following pharmacological inhibition of the cerebellar flocculus, to determine the cause of the abnormal vertical eye positions found in ataxic mice. The result will determine whether mice can be used to test treatments for downbeat nystagmus, a human manifestation of cerebellar disease that results in blurred vision. Specific Aim 2 tests the theory that ataxia in calcium channel mutants originates in disturbed Purkinje cell rhythmicity, through recordings of Purkinje cells in the flocculus and anterior vermis of normal mice and the CACNA1A mutant rocker. One goal of these recordings is to determine whether rocker Purkinje cells exhibit, as the rhythmicity theory predicts, rhythmicity intermediate between that of normal animals and the more severely affected CACNA1A mutant, tottering. Another goal of the recordings is to reassess whether CACNA1A mutant Purkinje cells modulate their firing normally in response to natural stimulation. This claim is central to the rhythmicity theory, but the experiments that support the claim may have been affected by sampling bias. Specific aim 3 assesses the therapeutic mechanisms of 4- aminopyridine, one of the drugs that has recently been shown to provide some benefits in cerebellar disorders. We will record eye movements in tottering following systemic and intrafloccular injections of 4- aminopyridine. Results of these experiments will allow us to test published speculations that aminopyridines exert their beneficial effects by restoring normal Purkinje cell activity.

描述（由申请人提供）：今天的神经科医生几乎没有什么疗法可以为患有小脑疾病导致的肢体共济失调、不平衡和视力障碍的患者提供治疗。此类患者在退伍军人中很常见，并且由于最近的军事行动中遭受的脑外伤而变得更加常见。然而，最近的进展表明可以开发出高效的药物：两种影响神经元钾通道的药物已被证明可以改善人类和小鼠的小脑缺陷，并可能为开发更有效和更耐受的药物提供起点。然而，它们的治疗效果的来源是有争议的。同样，一种新理论认为共济失调可能起源于小脑浦肯野细胞的节律性紊乱，建议进行药物开发，但该理论存在争议，需要更多研究。该项目将通过阐明小脑运动功能障碍的起源和一种现有治疗的机制，为药物开发奠定更好的基础。我们重点关注携带 P/Q (CaV2.1) 钙通道 CACNA1A 基因突变的小鼠的眼部运动异常，但结果应该适用于小脑功能障碍的其他原因和表现。具体目标 1 涉及 CACNA1A 突变体摇摇晃晃的眼球运动记录，以及药物抑制小脑絮球后正常小鼠的眼球运动记录，以确定共济失调小鼠中发现的异常垂直眼球位置的原因。结果将确定小鼠是否可用于测试悲观眼球震颤的治疗方法，悲观眼球震颤是一种导致视力模糊的小脑疾病的人类表现。具体目标 2 通过记录正常小鼠和 CACNA1A 突变摇杆的绒球和前蚓部中的浦肯野细胞，检验了钙通道突变体中的共济失调起源于浦肯野细胞节律性紊乱的理论。这些记录的目标之一是确定摇杆浦肯野细胞是否如节律性理论预测的那样表现出介于正常动物和受影响更严重的 CACNA1A 突变体（摇摇欲坠）之间的节律性。录音的另一个目标是重新评估 CACNA1A 突变型浦肯野细胞是否能够正常调节其放电以响应自然刺激。这一主张是节律性理论的核心，但支持这一主张的实验可能受到了抽样偏差的影响。具体目标 3 评估 4-氨基吡啶的治疗机制，该药物是最近被证明对小脑疾病有一定益处的药物之一。我们将记录全身注射 4-氨基吡啶和絮凝内注射后摇晃时的眼球运动。这些实验的结果将使我们能够检验已发表的推测，即氨基吡啶通过恢复正常的浦肯野细胞活性来发挥其有益作用。