Novel Approaches to Therapy of Muscle Ion Channelopathies

治疗肌肉离子通道病的新方法

• 批准号: 9895630
• 负责人: MARK M RICH
• 金额: $ 60.08万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895630
• 关键词: Action Potentials; Attention; Chloride Channels; Closure by clamp; Contracts; Data; Dependence; Development; Disease; Drops; Drug usage; Electrophysiology (science); Event; Exercise; Functional disorder; Generations; Goals; Health; Hour; Hyperkalemic periodic paralysis; In Vitro; Inherited; Ion Channel; Ions; Knock-out; Knockout Mice; Measurement; Measures; Modification; Molecular Genetics; Movement; Mus; Muscle; Muscle Weakness; Muscle function; Muscular Atrophy; Myopathy; Myotonia; Myotonia Congenita; Neurons; Patients; Percussion Myotonias; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Potassium Channel; Property; Role; Signal Transduction; Skeletal Muscle; Sodium Channel; Stretching; Symptoms; System; TRP channel; Testing; United States National Institutes of Health; Work; base; drug testing; effective therapy; efficacy testing; extracellular; gain of function mutation; hyperkalemia; improved; in vivo; loss of function mutation; motor disorder; motor function improvement; motor symptom; muscle stiffness; novel; novel strategies; novel therapeutics; prevent; response; voltage; voltage clamp

NIH abstract: Myotonia congenita (MC) and hyperkalemic periodic paralysis (HPP) are inherited skeletal muscle ion channel diseases. Despite initial descriptions of both diseases many years ago, effective and well tolerated therapy for both disorders has remained elusive. The reason for this is that a detailed understanding of mechanisms regulating muscle excitability in health and disease is lacking. A better understanding of mechanisms underlying muscle dysfunction in the non-dystrophic ion channelopathies is necessary to develop improved therapy for patients. While it is known that muscle in myotonia congenita is hyperexcitable due to reduction of ClC-1 current, the mechanisms underlying two motor symptoms suffered by patients remain poorly understood. The first is transient weakness in recessive forms of myotonia congenita (Becker disease). While the weakness lessens with continued exercise, it is likely a significant contributor to motor dysfunction. Weakness appears to be due to loss of muscle excitability, but the mechanism is unknown. The second symptom is stretch-induced (percussion) myotonia. As muscles must alternately contract and stretch during movement, stretch-induced myotonia may contribute significantly to stiffness. Currently, nothing is known about the mechanism triggering stretch-induced myotonia. We have discovered novel currents that underlie both weakness and stretch-induced myotonia. In Aims 1 and 2 our goal is characterize these currents and to test the efficacy of available blockers to develop novel therapy for motor dysfunction in myotonia congenita. In Aim 3 we extend this work to study of motor dysfunction in hyperkalemic periodic paralysis.

美国国立卫生研究院摘要： 先天性肌强直 (MC) 和高钾性周期性麻痹 (HPP) 是遗传性骨骼肌离子 经络疾病。尽管多年前就对这两种疾病进行了初步描述，但效果良好 这两种疾病的耐受治疗仍然难以捉摸。这样做的原因是，详细 缺乏对健康和疾病中调节肌肉兴奋性的机制的了解。更好的 了解非营养不良性离子通道病中肌肉功能障碍的机制 有必要为患者开发改进的治疗方法。 虽然已知先天性肌强直中的肌肉由于 ClC-1 电流的减少而过度兴奋， 患者遭受的两种运动症状的机制仍知之甚少。这 首先是隐性先天性肌强直（贝克尔病）的短暂性无力。虽然 随着持续锻炼，无力感会减轻，这可能是运动功能障碍的重要原因。 无力似乎是由于肌肉兴奋性丧失所致，但其机制尚不清楚。第二个 症状是牵拉引起的（叩击）肌强直。由于肌肉必须交替收缩和伸展 在运动过程中，拉伸引起的肌强直可能会导致僵硬。目前，没有什么 已知触发牵拉诱发性肌强直的机制。 我们发现了导致无力和拉伸引起的肌强直的新电流。目标中 1 和 2 我们的目标是表征这些电流并测试可用阻断剂的功效以开发 先天性肌强直运动功能障碍的新疗法。在目标 3 中，我们将这项工作扩展到研究 高钾性周期性麻痹的运动功能障碍。