Novel Approaches to Therapy of Muscle Ion Channelopathies

治疗肌肉离子通道病的新方法

• 批准号: 10398427
• 负责人: MARK M RICH
• 金额: $ 6.28万
• 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/10398427
• 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.

NIH摘要： Myotonia congenita（MC）和高血压周期性瘫痪（HPP）是遗传的骨骼肌离子 渠道疾病。尽管多年前对两种疾病的最初描述都有效且很好 两种疾病的耐受疗法仍然难以捉摸。原因是一个详细的 缺乏对调节健康和疾病肌肉兴奋性的机制的理解。更好 了解非疾病离子通道病中肌肉功能障碍的机制 对于改善患者的治疗是必要的。 虽然众所周知，由于Clc-1电流的降低，浓congenita的肌肉是过度兴奋的，但 患者遇到的两种运动症状的基础机制仍然很少了解。这 首先是Myotonia Congenita（Becker病）隐性形式的短暂弱点。而 通过继续运动的弱点减少了，这可能是导致运动功能障碍的重要贡献者。 弱点似乎是由于肌肉兴奋性的丧失所致，但该机制尚不清楚。第二个 症状是拉伸引起的（打击乐）肌瘤。因为肌肉必须交替收缩和伸展 在运动过程中，伸展引起的肌瘤可能对刚度有显着贡献。目前，什么都没有 关于触发拉伸诱发的肌瘤的机制已知。 我们发现了既是弱点又是伸展引起的肌肉症的新型水流。在目标中 1和2我们的目标是表征这些电流并测试可用阻滞剂开发的功效 Myotonia Congenita的运动功能障碍的新型疗法。在AIM 3中，我们将这项工作扩展到研究 高钾血症周期性瘫痪中的运动功能障碍。