Regulation of ion channels in the heart

心脏离子通道的调节

• 批准号: 9025418
• 负责人: Nipavan Chiamvimonvat
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025418
• 关键词: Adenylate Cyclase; Adrenergic Agents; Affect; Arrhythmia; Atrial Fibrillation; Atrial Function; Biochemical; Calcium-Activated Potassium Channel; Cardiac; Cardiovascular Diseases; Cells; Clinical; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Embolism; Fluorescence Resonance Energy Transfer; Functional disorder; Funding; Gene Targeting; Genetic; Genetic Polymorphism; Health; Heart; Heart Atrium; Heart failure; Human; Imaging Techniques; In Vitro; Incidence; Individual; Ion Channel; Laboratories; Ligands; Link; Mediating; Molecular; Molecular Models; Morbidity - disease rate; Mus; Muscle Cells; Neuroendocrine Cell; Neurons; Nodal; Patients; Pharmacotherapy; Play; Population; Process; Protein Isoforms; Publishing; Regulation; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Scaffolding Protein; Signal Transduction; Sinoatrial Node; Staging; Stroke; Techniques; Testing; Therapeutic; Tissues; United States; Ventricular; Veterans; Work; abstracting; aging population; atrioventricular node; base; caveolin-3; design; genome wide association study; heart rhythm; in vivo; insight; live cell imaging; molecular modeling; mortality; mouse model; multidisciplinary; null mutation; phosphoric diester hydrolase; sensor; trafficking; translational medicine; treatment strategy

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in the United States and in our veteran population. During the last funding cycle, we have identified several atrial-specifi ion channels including Cav1.3 (1D) L-type Ca2+ channel and small conductance Ca2+-activated K+ channels (SK or KCa2 channels) which play critical roles in the function of atrial myocytes as well as sinoatrial (SA) and atrioventricular (AV) nodes. Of clinical importance, we have demonstrated that SK channels are expressed and contribute significantly to the repolarization process in human atrial myocytes. For the current competing renewal application, we will focus our effort on the subcellular regulation of Ca2+ channels in ventricular myocytes and pacemaking cells. Embedded in our findings and the proposed project are relevant paradigm shifts that may be exploited in developing specific drugs for the treatment of cardiac arrhythmias. Specifically, we will test the central hypothesis that there is isoform-specific differential regulation of L-type Ca2+ current in ventricular myocytes and pacemaking cells by distinct isoforms of adenylyl cyclases (ACs). We will utilize new emerging techniques of live-cell imaging coupled with fluorescence resonance energy transfer (FRET)-based cAMP and protein kinase A (PKA) sensors to directly decipher the distinct subcellular localization and activities of different isoforms of ACs not only in ventricular myocytes but also in pacemaking cells. Indeed, we will take advantage of multidisciplinary techniques including in vivo and in vitro electrophysiologic recordings, live-cell imaging, and molecular modeling to determine the subcellular regulation of Ca2+ channels through distinct isoforms of ACs. Our proposed studies will expand our understanding of the specific subcellular localization and regulation of individual Ca2+ channels and how they might coordinate to mediate normal cardiac rhythm in vivo. Understanding the molecular and subcellular regulation of Ca2+ channels in the heart will set the stage for a new and more mechanistic approach for the treatment of cardiac arrhythmias and SA and AV node dysfunction, a common problem encountered in our veteran population.

描述(由申请人提供)： 心血管疾病是美国和我们退伍军人人口发病率和死亡率的主要原因。在上一个资助周期中，我们发现了几种心房特异通道，包括CaV1.3(1D)L型钙通道和小电导钙激活钾通道(SK或KCa通道)，它们在心房肌细胞以及窦房结(SA)和房室结(AV)的功能中起关键作用。具有临床意义的是，我们已经证明SK通道在人心房肌细胞的复极过程中有显著的表达和贡献。对于目前竞争性的更新应用，我们将集中精力研究心室肌细胞和起搏细胞中钙离子通道的亚细胞调控。在我们的发现和拟议的项目中嵌入了相关的范式转变，可以利用这些转变来开发治疗心律失常的特定药物。具体地说，我们将检验这一中心假设，即不同亚型的腺苷环化酶(Acs)对心室肌细胞和起搏细胞的L型钙电流存在异构体特异性的差异性调节。我们将利用新的活细胞成像技术，结合基于荧光共振能量转移(FRET)的cAMP和蛋白激酶A(PKA)传感器来直接破译不同的亚细胞定位和活性 不同亚型的ACS不仅存在于心肌细胞中，而且存在于起搏细胞中。事实上，我们将利用包括体内和体外电生理记录、活细胞成像和分子建模在内的多学科技术来确定通过不同亚型的ACS对钙离子通道的调节。我们建议的研究将扩大我们对个体特定亚细胞定位和调节的理解。 钙离子通道以及它们在体内如何协调调节正常的心率。了解心脏中钙离子通道的分子和亚细胞调控，将为治疗心律失常和房室结和房室结功能障碍的新的、更具机械性的方法奠定基础，这是我们退伍军人群体中遇到的常见问题。