Novel Approaches to Therapy of Muscle Ion Channelopathies

美国国立卫生研究院摘要： 先天性肌强直症(MC)和高钾性周期性麻痹(HPP)是遗传性骨骼肌离子 经络疾病。尽管许多年前对这两种疾病的初步描述都是有效的和良好的 对这两种疾病的耐受治疗仍然难以捉摸。这样做的原因是一个详细的 对健康和疾病中肌肉兴奋性的调节机制缺乏了解。更好的 对非营养不良离子通道病肌肉功能障碍机制的认识 是为患者开发改进的治疗方法所必需的。 虽然众所周知，由于ClC-1电流的减少，先天性肌强直的肌肉是过度兴奋的， 患者遭受的两种运动症状背后的机制仍然知之甚少。这个 首先是隐性形式的先天性肌强直(贝克氏病)的一过性无力。而当 虚弱会随着持续的运动而减轻，这可能是导致运动功能障碍的一个重要因素。 无力似乎是由于肌肉兴奋性的丧失，但机制尚不清楚。第二 症状是牵张性(敲击性)肌强直。因为肌肉必须交替收缩和伸展 在运动过程中，牵张引起的肌强直可能对僵硬有很大影响。目前，什么都没有 已经知道了引发牵张性肌强直的机制。 我们已经发现了新的电流，这些电流既是无力的基础，也是牵张性肌强直的基础。在AIMS中 1和2我们的目标是确定这些电流的特征，并测试可用的阻滞剂的疗效 先天性肌强直症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 高血钾性周期性麻痹患者的运动功能障碍。

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.