Defining novel mechanisms for human arrhythmia

定义人类心律失常的新机制

• 批准号: 10525258
• 负责人: Peter J. Mohler
• 金额: $ 80.96万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525258
• 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; Disease; Functional disorder; Funding; Genetic; Goals; Health; Heart; Heart Diseases; Human; Ion Channel; Laboratories; Lead; Learning; Membrane; National Heart, Lung, and Blood Institute; Newly Diagnosed; Oxidases; Pathway interactions; Patients; 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; cell growth regulation; design; human disease; improved; innovation; insight; mortality; novel; pharmacologic; 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。 发达国家的死亡原因。不幸的是，可以说是最后一次重大的“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）。另一方面，治疗剂 治疗心脏兴奋障碍（心律失常）的疗效有限，甚至脱靶 心律失常。尽管有大量负面的临床数据，但兴奋的细胞研究人员基本上仍然 专注于相同的范式——针对心脏离子通道的药物疗法。我们认为 只有通过对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 心肌细胞。此外，我们还了解到这些蛋白质作为关键的中央膜节点 调节心脏的正常信号传导。最后，也是最重要的，我们了解到这些功能障碍 途径导致潜在致命的先天性和获得性室性心律失常。 我们的长期目标是发现调节心血管细胞的新型综合机制 兴奋性和信号传导。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，但建议将这些研究迅速扩展到具有多种相互作用的结构-电学-的新系统 信号系统。我们的实验室在识别新的细胞途径方面发挥了积极的领导作用 基于人类临床、组织和遗传数据的细胞兴奋性调节。此外，我们还有 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 复杂脊椎动物心肌细胞中电信号传导的机制。这种方法有 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 针对这些疾病的有效的患者选择性疗法。如果成功获得 NHLBI 的资助 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。

项目成果

Response by El Refaey et al to Letter Regarding Article, "Protein Phosphatase 2A Regulates Cardiac Na+ Channels".

El Refaey 等人对有关文章“蛋白磷酸酶 2A 调节心脏 Na 通道”的信件的回复。

• DOI: 10.1161/circresaha.119.314938
• 发表时间: 2019
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: ElRefaey,Mona;Musa,Hassan;Smith,SakimaA;Binkley,PhilipF;Bradley,Elisa;Hund,ThomasJ;Mohler,PeterJ
• 通讯作者: Mohler,PeterJ

Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart.

• DOI: 10.1161/circulationaha.115.021165
• 发表时间: 2016-08-09
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Li N;Csepe TA;Hansen BJ;Sul LV;Kalyanasundaram A;Zakharkin SO;Zhao J;Guha A;Van Wagoner DR;Kilic A;Mohler PJ;Janssen PM;Biesiadecki BJ;Hummel JD;Weiss R;Fedorov VV
• 通讯作者: Fedorov VV

In Vivo Genome Editing Restores Dystrophin Expression and Cardiac Function in Dystrophic Mice.

• DOI: 10.1161/circresaha.117.310996
• 发表时间: 2017-09-29
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: El Refaey M;Xu L;Gao Y;Canan BD;Adesanya TMA;Warner SC;Akagi K;Symer DE;Mohler PJ;Ma J;Janssen PML;Han R
• 通讯作者: Han R

Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes.

• DOI: 10.3390/cells11193049
• 发表时间: 2022-09-29
• 期刊: Cells
• 影响因子: 6

Pharmacologic Approach to Sinoatrial Node Dysfunction.

• DOI: 10.1146/annurev-pharmtox-031120-115815
• 发表时间: 2021-01-06
• 期刊: Annual review of pharmacology and toxicology
• 影响因子: 12.5
• 作者: Mesirca P;Fedorov VV;Hund TJ;Torrente AG;Bidaud I;Mohler PJ;Mangoni ME
• 通讯作者: Mangoni ME