The Role of Junctophilin Type 2 in Cardiac Node Automaticity

2 型亲结蛋白在心脏结自律性中的作用

• 批准号: 10178073
• 负责人: Andrew P. Landstrom
• 金额: $ 15.39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178073
• 关键词: Acute; Address; Affect; Arrhythmia; Biochemical; Biochemistry; Biological Assay; Calcium; Calcium Signaling; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cardiac pacemaker; Cardiovascular Diseases; Cardiovascular system; Cell membrane; Cells; Chemicals; Child; Child Care; Childhood; Clinical; Coupled; Development; Disease; Ectopic Junctional Tachycardia; Electrophysiology (science); Enzymes; Etiology; Experimental Models; Follow-Up Studies; Foundations; Frequencies; Fright; Functional disorder; Funding; Grant; HCN4 gene; Heart; Heart Rate; Heart failure; Human; Image; Impairment; Investigation; Ion Channel; Knowledge; Learning; Life; Lipid Bilayers; Literature; Mediating; Medical; Modeling; Molecular; Molecular Target; Mus; Muscle Cells; Nodal; Nodal Arrhythmia; Operative Surgical Procedures; Pacemakers; Pathologic; Patient Care; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphorylation; Phosphotransferases; Physicians; Physiology; Play; Postoperative Period; Probability; Proteins; Regulation; Research Personnel; Rest; Role; RyR2; Scientist; Signal Transduction; Sinoatrial Node; Sinus Tachycardia; Sodium-Calcium Exchanger; Structural Protein; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; TimeLine; Tissues; Toxic effect; Training; atrioventricular node; base; calmodulin-dependent protein kinase II; career; clinically translatable; experience; in vitro testing; in vivo; inducible gene expression; inhibitor/antagonist; insight; junctophilin; knock-down; mouse model; novel therapeutics; patch clamp; single cell analysis; small molecule; targeted treatment; therapeutic evaluation; tool

ABSTRACT Diseases of the nodal tissue of the heart can be life threatening, particularly in the young. Nodal tissue spontaneously depolarizes serving as a pacemaker for cardiac contraction, yet despite this central role critical for survival, the cause of nodal dysfunction is poorly understood. This lack of mechanistic understanding has impaired development of efficacious and selective pharmacotherapies, and as a correlate, drugs levied against nodal disease carry significant toxicity for the patient and can still be entirely ineffective. While the nodal automaticity was traditionally thought to be controlled by ion channels on the plasma membrane, there is a growing body of evidence that calcium-signaling within the cell may regulate spontaneous depolarization – its automaticity. Previous investigation has shown that calcium leak from the internal calcium release channel, RyR2, may be associated with increased nodal firing, thus understanding this so-called “calcium clock” can provide additional molecular targets for nodal-specific novel therapeutics. I have created a mouse model of nodal-specific expression silencing of a protein called junctophilin-2 (JPH2), which I have previously shown to be critical to effective calcium- handling in the contractile myocyte, as a tool for studying a dysfunctional calcium clock. I have found that this mouse has an elevated heart rate at rest and a rapidly firing atrioventricular node which causes an arrhythmia known as accelerated junctional rhythm (AJR). I propose 3 specific aims to test our central hypothesis that reduced JPH2 expression results in CaMKII-mediated increase in RyR2 gating which causes increased store calcium leak and drives increased nodal automaticity and AJR. My aims are to 1) utilize confocal-based calcium imaging of isolated nodal cells from HCN4:shJPH2 mice, coupled with RyR2 single channel recordings to determine whether reduced JPH2 expression causes increased calcium leak with higher RyR2 channel opening probability; 2) apply known chemical inhibitors of RyR2 to isolated single cells and HCN4:shJPh2 mice to assess whether calcium leak can be normalized and AJR effectively treated; and 3) conduct biochemistry from isolated nodal tissue to determine the role of CaMKII signaling, including its downstream phosphorylation targets, in regulation of nodal firing. I expect that completion of these aims will yield clinically translatable mechanistic insight into the “calcium clock” of the node. Through exploration of the first murine model of isolated cardiac nodal disease in the literature, these aims will provide a substrate from which to test novel therapeutic agents specifically targeted at perturbed calcium-signaling in nodal tissue. Completion of this 5-year training grant will allow me to combine my clinical training in pediatric electrophysiology with exploration of the molecular mechanisms of nodal disease and become an independently funded physician-scientist committed to helping children with arrhythmias.

摘要

项目成果

Early experience with intravenous sotalol in children with and without congenital heart disease.

患有和不患有先天性心脏病的儿童静脉注射索他洛尔的早期经验。

• DOI: 10.1016/j.hrthm.2018.07.010
• 发表时间: 2018
• 期刊: Heart rhythm
• 影响因子: 5.5
• 作者: Valdés,SantiagoO;Miyake,ChristinaY;Niu,MaryC;delaUz,CaridadM;Asaki,SYukiko;Landstrom,AndrewP;Schneider,AndrewE;Rusin,CraigG;Patel,Raajen;Lam,WilsonW;Kim,JeffreyJ
• 通讯作者: Kim,JeffreyJ

ATP1A3-Encoded Sodium-Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia.

• DOI: 10.1161/jaha.120.019887
• 发表时间: 2021-09-07
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Moya-Mendez ME;Ogbonna C;Ezekian JE;Rosamilia MB;Prange L;de la Uz C;Kim JJ;Howard T;Garcia J;Nussbaum R;Truty R;Callis TE;Funk E;Heyes M;Dear GL;Carboni MP;Idriss SF;Mikati MA;Landstrom AP
• 通讯作者: Landstrom AP