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）：当今的神经科医生几乎没有疗法为患有小脑疾病造成的肢体共济失调，失衡和视力障碍的患者提供疗法。此类患者在退伍军人人口中很普遍，并且由于最近的军事行动遭受了创伤性脑损伤而变得越来越多。然而，最近的发展表明可以开发高效的药物：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，并可能提供起点以开发出更有效和耐受的药物。但是，其治疗作用的来源值得讨论。同样，一种新理论可以源于小脑普林吉细胞的干扰节奏性，提出了药物开发的程序，但该理论是有争议的，需要进行更多的研究。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来为药物开发提供更好的基础。我们专注于携带P/Q（CAV2.1）钙通道的CACNA1A基因突变的小鼠的眼运动异常，但结果应适用于小脑功能障碍的其他原因和表现。具体的目标1涉及Cacna1a突变体中的眼动记录，并且在药理学抑制小脑絮凝物后正常小鼠中，以确定产生性产生小鼠中异常垂直眼睛位置的原因。结果将确定小鼠是否可以用于测试下be虫的治疗方法，这是小脑疾病的人类表现，导致视力模糊。具体目标2检验了钙通道突变体中的（钙通道突变体中的共济失调）源于受干扰的浦肯野细胞的节奏性，通过记录普通小鼠的泡沫和前刺和cacna1a突变体摇杆的purkinje细胞的记录。这些录音的目标之一是确定摇滚浦肯野细胞是否表现出来，如节奏理论所预测的那样，正常动物与更严重影响的cacna1a突变体之间的节奏中间是to乱的。录音的另一个目标是重新评估Cacna1a突变体Purkinje细胞是否正常对自然刺激进行调节。该主张是节奏理论的核心，但是支持该主张的实验可能受到采样偏见的影响。特定目标3评估了4-氨基吡啶的治疗机制，4-氨基吡啶的治疗机制最近被证明是在小脑疾病中提供一些好处的药物。我们将在全身和全面注射4-氨基吡啶的全身性和全面注射后记录眼动运动。这些实验的结果将使我们能够测试已发表的猜测，即氨基吡啶通过恢复正常的Purkinje细胞活性来发挥其有益作用。