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 高钾血症周期性瘫痪（HyperKPP）是遗传性骨骼肌疾病的家族之一 离子通道病。 HyperKPP患者在骨骼肌NAV1.4钠通道中有突变。 重要的是，患者遭受了肌肉瘫痪和无力持续时间到几分钟的间歇性攻击。 尽管确定了负责的基因，但弱点攻击的基础机制仍然很差 理解，当前的疗法仅适度有效，并且具有副作用。鼠标模型 已经产生了HyperKPP，这概括了患者疾病的关键方面。鼠标 模型将用于识别导致激发收缩偶联失败的机制 膜电位的病理去极化。这些相关研究的范围将从整个整体范围 肌肉力记录至单纤维中CA瞬变的测量。一种新技术允许 完整的单肌纤维的动作电位和CA瞬变的同时，细胞内记录 肌肉。总体目标是解决当前对HyperKPP的方面不足并开发新颖的方面 更好疗法的策略。这将以三个具体目标进行： 1）确定去极化引起的激发收缩失败的机制 正常肌肉中的耦合（ECC）：试点数据表明ECC的失败比以前更为复杂 怀疑。所提出的相关研究将阐明ECC之前发生的事件。 2）确定膜电位的去极化导致ECC失败的程度 在Hyperpp中。拟议的研究将确定突变肌肉过度去极化是否可以完全 解释弱点。 HyperKPP与野生型小鼠中的一系列电生理实验将解决 这个基本问题。 3）检查具有更有选择性阻滞剂的去极化电流的块作为有效的疗法 HyperKpp。如果HyperKpp的主要原因是肌肉去极化，则阻塞去极化电流 应提供有效的疗法。但是，临床研究表明当前的NA通道阻滞剂是 对患者无效。 鉴定导致去极化引起的HyperKPP中无力无力的机制对 肌肉去极化的所有疾病都会导致无力。如果发现有效治疗 HyperKPP小鼠模型的弱点，将来的工作将致力于将发现转化为临床试验 在患者中。