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Novel Approaches to Therapy of Muscle Ion Channelopathies

治疗肌肉离子通道病的新方法

基本信息

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
项目类别：
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

项目摘要

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.

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