Defining novel mechanisms for human arrhythmia

定义人类心律失常的新机制

• 批准号: 10078625
• 负责人: Peter J. Mohler
• 金额: $ 81.85万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-06 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078625
• 关键词: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Ankyrins; Arrhythmia; Award; Biological Models; Biology; Cardiac; Cardiac Myocytes; Cardiovascular system; Carrier Proteins; Cells; Clinical; Clinical Data; Complex; Data; Defect; Developed Countries; Diagnosis; Disease; Functional disorder; Funding; Genetic; Goals; Health; Heart; Heart Diseases; Human; Ion Channel; Laboratories; Lead; Membrane; National Heart, Lung, and Blood Institute; Oxidases; Pathway interactions; Patients; Pharmacology; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Play; Proteins; Pump; Research Personnel; Role; Signal Transduction; Signaling Protein; Spectrin; Structural Protein; Structure; System; Therapeutic Agents; Tissues; Ventricular; Ventricular Arrhythmia; base; cell growth regulation; design; human disease; improved; innovation; insight; mortality; novel; sudden cardiac death; targeted treatment

Abstract Defects in cardiac excitability are the basis for human arrhythmia and sudden cardiac death, a leading cause of mortality in developed countries. Unfortunately, arguably the last major “game-changing” breakthroughs in electrical cardiomyocyte biology and cardiac signaling for human health were the beta- blocker (discovered in the 1950s) and `ACE' inhibitor (in the 1970s). On the other hand, therapeutic agents to treat disorders of cardiac excitation (arrhythmias) are plagued by limited efficacy and even off-target pro- arrhythmia. Despite a wealth of negative clinical data, excitable cell researchers have largely remained focused on the same paradigm - pharmacological therapies targeting cardiac ion channels. We contend that improved therapies will only arise through a more sophisticated, working understanding of interactions between structural proteins (such as ankyrins), electrical proteins (ion channels, pumps & exchangers) and signaling systems (kinases, phosphatases, oxidases). Our studies discovered that ankyrin and spectrin proteins, previously considered static membrane adapters, play dynamic roles in ion channel, transporter, and signaling protein targeting in ventricular cardiomyocytes. Further, we have learned that these proteins serve as critical central membrane nodes to regulate normal signaling in heart. Finally, and most importantly, we have learned that dysfunction in these pathways results in potentially fatal forms of both congenital and acquired ventricular arrhythmia. Our long-term goal is to discover novel integrated mechanisms for regulating cardiovascular cell excitability and signaling. We have used the informative case of ankyrins and spectrins as a tractable starting point, but propose to rapidly extend these studies to new systems with diverse interacting structure-electrical- signaling systems. Our laboratory has taken an active lead in the identification of new cellular pathways for regulation of cellular excitability based on human clinical, tissue, and genetic data. In addition, we have pushed innovation in the field through the use of physiologically-relevant model systems to study the mechanisms underlying electrical signaling in the complex vertebrate cardiomyocyte. This approach has ultimately culminated in an ability to not only diagnose new forms of potentially fatal arrhythmia, but to design effective patient-selective therapies for these diseases. If successful in obtaining funding from the NHLBI Outstanding Investigator Award, we will continue to pursue scientific studies with the potential to create new, cell-specific insights for improved understanding of cardiac excitability with direct relevance for congenital and acquired human disease.

抽象的 心脏兴奋性缺陷是人类心律失常和心源性猝死的基础，这是导致人类心律失常和心源性猝死的主要原因。 不幸的是，这可以说是最后一个重大的“游戏规则改变”。 心肌细胞电生物学和心脏信号传导对人类健康的突破是β- 阻滞剂（20 世纪 50 年代发现）和“ACE”抑制剂（20 世纪 70 年代）。 治疗心脏兴奋障碍（心律失常）的方法受到疗效有限甚至脱靶的困扰。 尽管有大量负面的临床数据，但兴奋性细胞研究人员基本上仍然存在。 我们认为，重点关注同一范式——针对心脏离子通道的药物疗法。 只有通过对两者之间的相互作用进行更复杂、更有效的理解，才会出现改进的治疗方法。 结构蛋白（如锚蛋白）、电蛋白（离子通道、泵和交换器）和信号传导 系统（激酶、磷酸酶、氧化酶）。 我们的研究发现锚蛋白和血影蛋白（以前被认为是静态膜） 适配器，在心室的离子通道、转运蛋白和信号蛋白靶向中发挥动态作用 此外，我们还了解到这些蛋白质是心肌细胞的关键中央膜节点。 最后，也是最重要的是，我们了解到这些功能障碍。 结果导致先天性和获得性室性心律失常的潜在致命形式。 我们的长期目标是发现调节心血管细胞的新型综合机制 我们使用锚蛋白和血影蛋白的信息丰富的案例作为易于处理的起点。 点，但建议将这些相互作用的研究迅速扩展到具有不同结构-电学-的新系统 我们的实验室在识别新的细胞通路方面发挥了积极作用。 此外，我们还有基于人类临床、组织和遗传数据的细胞兴奋性调节。 通过使用生理相关模型系统来研究该领域，推动了该领域的创新 这种方法揭示了复杂脊椎动物心肌细胞中电信号传导的机制。 最终不仅能够诊断潜在致命性心律失常的新形式，而且能够设计 如果成功获得 NHLBI 的资助，则可以对这些疾病进行有效的患者选择性治疗。 杰出研究者奖，我们将继续追求有潜力创造新的、 细胞特异性的见解，以提高对心脏兴奋性的理解，这与先天性和 获得性人类疾病。