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Mechanism-inspired Strategies to Prevent Pathogenic Late Na Current in Cardiac Arrhythmias

预防心律失常致病性晚钠电流的机制启发策略

基本信息

批准号：
10587033
负责人：
Manu Ben Johny
金额：
$ 57.58万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-17 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587033
关键词：
Action Potentials Adult Alternative Splicing Amino Acids Arrhythmia Binding Sites Biological Assay Biophysics Cardiac Cardiac Myocytes Cardiomyopathies Cells Clinical Closure by clamp Data Disease Dizziness Doctor of Philosophy Engineering Etiology Exhibits Fibroblast Growth Factor Fibroblasts Fluorescence Resonance Energy Transfer Functional disorder Future Heart Heart Diseases Heart failure Homeostasis Human Kinetics Life Link Long QT Syndrome Maps Measurement Molecular Morphology Muscle Cells Mutagenesis Mutation Names Optics Pathogenicity Pathology Patients Penetration Peptides Pharmacology Phase Phenotype Phosphorylation Physiological Physiology Post-Translational Protein Processing Protein Isoforms Proteins RNA Splicing Regulation Rodent Role Scheme Specificity Syndrome System Therapeutic Transgenic Mice Variant Ventricular Viral clinically relevant effectiveness evaluation fluorescence imaging heart function induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes inhibitor insight novel preservation prevent protective factors stem voltage

项目摘要

PROJECT SUMMARY PI: Manu Ben-Johny, Ph.D. NaV1.5 channels are fundamentally involved in the normal function and pathophysiology of the heart. NaV1.5 dysfunction is linked to a variety of life-threatening cardiac diseases, including congenital and acquired cardiac arrhythmias, cardiomyopathies, and heart failure. An emerging commonality for these pathologies is increased late Na current, that results in sustained Na influx during the plateau phase of the cardiac action potential. Understanding mechanisms that regulate late Na current is pivotal to understanding NaV1.5 dysfunction in cardiac pathophysiology and for developing long-sought pharmacology. Our recent studies and preliminary data suggest that late Na current is powerfully tuned by a Na channel modulator named fibroblast growth factor homologous factor (FHF) that is endogenous to cardiomyocytes. Yet, how FHF accomplishes this important mode of NaV1.5 regulation and its relevance to disease pathogenic mechanisms is not fully determined. In this collaborative project, we seek (1) to dissect the molecular mechanism of FHF regulation of late Na current, and (2) to identify the physiological and pathophysiological relevance of this modulatory scheme. Armed with in depth mechanistic insights, we seek to engineer novel peptide-based inhibitors of late Na current. In particular, as FHF undergoes extensive alternative-splicing, we evaluate isoform-specificity of late Na current regulation using a novel FRET assay and through extensive single-channel analysis. To probe the physiological impact of FHF regulation of late Na current, we virally manipulate FHF levels in cardiomyocytes differentiated from long-QT and mixed-syndrome patient-derived induced pluripotent stem cells as well as transgenic mouse ventricular myocytes. In so doing, this proposal promises new biophysical and physiological insights into modulation of cardiac NaV1.5 and inform upon mechanisms underlying variable clinical manifestations of Na channelopathies.

项目总结派：Manu Ben-Johny，博士。 NAV1.5通道从根本上参与心脏的正常功能和病理生理。NaV1.5 功能障碍与各种危及生命的心脏疾病有关，包括先天性和获得性心脏疾病。心律失常、心肌病和心力衰竭。这些病理的一个新出现的共性增加了晚期钠电流，导致心脏动作电位平台期持续的钠内流。了解晚期钠电流的调节机制对于理解NAV1.5功能障碍至关重要。心脏病理生理学和开发长期寻求的药理学。我们最近的研究和初步数据提示晚期钠电流受一种名为成纤维细胞生长因子的钠通道调节剂的有效调节心肌细胞内源性的同源因子(FHF)。然而，FHF是如何实现这一重要的 NaV1.5的调控方式及其与疾病致病机制的相关性尚未完全确定。在这合作项目，我们寻求(1)剖析FHF调节晚期Na电流的分子机制，以及 (2)确定这一调节机制的生理学和病理生理学相关性。以纵深武装起来机制洞察，我们寻求设计新的基于多肽的晚期钠电流抑制剂。特别是，作为FHF，经历了广泛的选择性剪接，我们使用一种新的FRET分析和通过广泛的单通道分析。探讨短暂性心衰的生理影响晚期钠电流的调节，我们通过病毒操纵从长QT和长QT分化的心肌细胞的FHF水平混合综合征患者来源的诱导多能干细胞以及转基因小鼠心脏肌细胞。在这样做的过程中，这一提议有望为调节脑功能提供新的生物物理和生理见解。心脏NaV1.5，并告知钠通道病不同临床表现的潜在机制。