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.

项目总结/摘要 高钾型周期性麻痹（HyperKPP）是一个家族的遗传性骨骼肌疾病，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，患者会遭受间歇性的肌肉麻痹和虚弱，持续数分钟至数天。 尽管已经确定了致病基因，但虚弱发作的潜在机制仍然不清楚 目前的治疗方法只有适度的有效性，并且有副作用。的小鼠模型 HyperKPP已经产生，它概括了患者疾病的关键方面。鼠标 模型将被用来确定机制，有助于失败的兴奋收缩耦合所造成的 膜电位的病理性去极化。这些相关的研究将从体外整体- 肌肉力量记录下降到测量钙瞬变在单纤维。一项新技术允许 同时，细胞内记录动作电位和钙瞬变的单一肌纤维在一个完整的 肌肉.总体目标是解决目前对HyperKPP知之甚少的问题，并开发新的 更好的治疗策略。这将在三个具体目标下进行： 1)确定去极化引起兴奋收缩失败的潜在机制 正常肌肉中的偶联（ECC）：初步数据表明ECC的失败比以前更复杂 疑似建议的相关研究将阐明ECC失败之前的事件。 2)确定膜电位去极化对ECC失败的影响程度 在HyperPP中。拟议的研究将确定突变肌肉的过度去极化是否可以完全 说明弱点。HyperKPP与野生型小鼠的一系列电生理学实验将解决 这个基本问题。 3)检查用更具选择性的阻滞剂阻断去极化电流作为有效治疗 HyperKPP。如果HyperKPP的主要原因是肌肉去极化，则阻断去极化电流 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 对患者无效。 识别有助于HyperKPP中去极化诱导的弱点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 HyperkPP小鼠模型的弱点，未来的工作将致力于将发现转化为临床试验 在病人身上。