Treating Hyperkalemic Periodic Paralysis

治疗高钾性周期性麻痹

• 批准号: 10537584
• 负责人: Christopher Dupont
• 金额: $ 4.41万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537584
• 关键词: Action Potentials; Address; Calcium; Clinical; Clinical Research; Clinical Trials; Cognition Disorders; Collaborations; Complex; Conotoxin; Coupling; Data; Disease; Disease model; Electrophysiology (science); Event; FDA approved; Failure; Family; Fiber; Future; Generations; Genes; Goals; Hyperkalemic periodic paralysis; Infusion procedures; Inherited; Ions; Knowledge; Measurement; Measures; Membrane Potentials; Modeling; Molecular Conformation; Mus; Muscle; Muscle Fibers; Muscular Atrophy; Mutation; Myopathy; Napping; Pain; Paralysed; Pathologic; Patients; Pharmaceutical Preparations; Public Health; Research Design; Role; Series; Skeletal Muscle; Sodium Channel; Specificity; Study models; Techniques; Testing; Translating; Wild Type Mouse; Work; channel blockers; effective therapy; experience; experimental study; gain of function mutation; mouse model; mutant; novel; novel strategies; novel therapeutics; prevent; side effect; therapy development; voltage clamp

Project Summary/Abstract Hyperkalemic Periodic Paralysis (HyperKPP) is one of a family of inherited skeletal muscle diseases known as the ion channelopathies. HyperKPP patients have mutations in the skeletal muscle Nav1.4 sodium channel. Importantly, patients suffer intermittent attacks of muscle paralysis and weakness lasting from minutes to days. Despite identification of the gene responsible, mechanisms underlying the attacks of weakness remain poorly understood, and current therapies are only modestly effective and have side effects. A mouse model of HyperKPP has been generated, which recapitulates the key aspects of the disorder in patients. The mouse model will be used to identify mechanisms contributing to failure of excitation contraction coupling caused by pathologic depolarization of the membrane potential. These correlated studies will range from ex vivo whole- muscle force recordings down to measurement of Ca transients in single fibers. A new technique allows for simultaneous, intracellular recordings of action potentials and Ca transients of single muscle fibers in an intact muscle. The overall goal is to address currently poorly understood aspects of HyperKPP and to develop novel strategies for better therapies. This will be done in three Specific Aims: 1) Determine the mechanisms underlying depolarization-induced failure of excitation contraction coupling (ECC) in normal muscle: Pilot data suggests failure of ECC is more complex than previously suspected. The proposed correlated studies will elucidate the events preceding failure of ECC. 2) Determine the extent to which depolarization of the membrane potential contributes to failure of ECC in HyperPP. The proposed studies will determine whether excessive depolarization of mutant muscle can fully account for weakness. A series of electrophysiology experiments in HyperKPP vs. wild-type mice will address this fundamental question. 3) Examine block of depolarizing current with a more selective blocker as an effective therapy for HyperKPP. If the primary cause of HyperKPP is muscle depolarization, blocking the depolarizing current should provide effective therapy. However, clinical studies suggest that the current Na channel blockers are not effective in patients. Identification of mechanisms contributing to depolarization-induced weakness in HyperKPP has implications for all diseases in which depolarization of muscle contributes to weakness. If effective therapies are found to treat weakness in the mouse model of HyperkPP, future work will be directed at translating findings to clinical trials in patients.

项目摘要/摘要 高钾性周期性麻痹(HyperKPP)是一种遗传性骨骼肌疾病家族，被称为 离子通道病。HyperKPP患者骨骼肌Nav1.4钠通道发生突变。 重要的是，患者会间歇性发作肌肉瘫痪和虚弱，持续时间从几分钟到几天不等。 尽管确定了导致虚弱发作的基因，但其潜在的机制仍然很差。 了解，目前的治疗方法只有一定的效果，而且有副作用。一种小鼠模型 已经生成了HyperKPP，它概括了患者疾病的关键方面。鼠标 模型将被用来确定导致激励收缩耦合失败的机制 病理性的膜电位去极化。这些相关研究的范围将从体外整体- 肌力记录可以精确到测量单个纤维中的钙瞬变。一种新技术允许 单根肌纤维动作电位和钙瞬变的细胞内同步记录 肌肉。总体目标是解决目前对HyperKPP知之甚少的方面，并开发新的 更好的治疗策略。这项工作将有三个具体目标： 1)确定去极化导致兴奋收缩失败的机制 正常肌肉中的偶联(ECC)：试点数据表明ECC的故障比以前更复杂 有嫌疑。拟议的相关研究将阐明ECC失败之前的事件。 2)确定膜电位的去极化对ECC失效的影响程度 在HyperPP中。拟议中的研究将确定突变肌肉的过度去极化是否能完全 解释软弱的原因。HyperKPP与野生型小鼠的一系列电生理学实验将解决 这个根本性的问题。 3)使用更具选择性的阻滞剂检查去极化电流的阻断，作为治疗的有效方法 HyperKPP。如果HyperKPP的主要原因是肌肉去极化，那么阻断去极化电流 应该能提供有效的治疗。然而，临床研究表明，目前的钠通道阻滞剂是 对病人无效。 识别导致HyperKPP去极化诱导的弱的机制具有以下意义 肌肉去极化导致虚弱的所有疾病。如果找到有效的治疗方法 在HyperkPP小鼠模型的弱点下，未来的工作将致力于将发现转化为临床试验 在病人身上。