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

• 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
• 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

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)： 今天的神经学家几乎没有治疗方法来为患有肢体共济失调、失衡和因小脑疾病而导致的视力障碍的患者提供治疗。这类患者在退伍军人中很常见，由于在最近的军事行动中遭受创伤性脑损伤，这种情况变得更加常见。然而，最近的发展表明，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仍有争议。同样，一种新的理论认为，共济失调可能起源于小脑浦肯野细胞节律性的紊乱，这一理论建议了药物开发的程序，但该理论存在争议，需要更多的研究。该项目将通过阐明小脑运动功能障碍的起源和现有治疗方法的机制，为药物开发奠定更好的基础。我们专注于携带P/Q(CaV2.1)钙通道CACNA1A基因突变的小鼠的眼球运动异常，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包括CACNA1a突变体摇摇欲坠的眼球运动记录，以及药物抑制小脑小叶后正常小鼠的眼球运动记录，以确定在共济失调小鼠中发现的异常垂直眼位的原因。这一结果将决定小鼠是否可以用于测试眼球震颤的治疗方法，这是一种人类小脑疾病的表现，会导致视力模糊。特定目的2通过记录正常小鼠的小叶和前棘以及CACNA1a突变摇杆中的浦肯野细胞，验证钙通道突变的共济失调起源于浦肯野细胞节律性紊乱的理论。这些记录的一个目标是确定摇摆浦肯野细胞是否像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突变的节律性之间的节律性摇摇欲坠。录音的另一个目标是重新评估CACNA1A突变的浦肯野细胞是否对自然刺激做出了正常的反应。这一论断是节奏性理论的核心，但支持这一论断的实验可能受到抽样偏差的影响。具体目的3评估4-氨基吡啶的治疗机制，4-氨基吡啶是最近被证明对小脑疾病有一些益处的药物之一。我们将记录全身注射和绒毛内注射4-氨基吡啶后摇摇欲坠的眼球运动。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动而发挥其有益作用。