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。在上一个融资周期中，我们确定了几个房间特异性离子通道，包括CAV1.3（1D）L型Ca2+通道和小电导Ca2+激活的K+通道（SK或KCA2通道），这些通道（SK或KCA2通道）在心脏肌细胞和sinoatial（Sanoatial（Sa）和AV）和AV）中起着至关重要的作用。非常重要的是，我们已经证明了SK通道表达并显着促进了人心房心肌的复极过程。 对于当前的竞争续订应用，我们将把精力集中在心室心肌细胞和起搏细胞中Ca2+通道的亚细胞调节上。嵌入在我们的发现中和拟议项目中的是相关的范式转移，这些范式可以在开发特定药物以治疗心律不齐的特定药物中。具体而言，我们将测试中心假设：在心室肌细胞和起搏细胞中，通过腺苷酸环化酶（ACS）有不同的同工型在心室肌细胞和起搏细胞中L型Ca2+电流的差分调节。我们将利用活细胞成像的新的新兴技术，再加上荧光共振能量转移（FRET）的营地和蛋白激酶A（PKA）传感器（PKA）传感器，直接破译独特的亚细胞定位以及 AC的不同同工型不仅在心室肌细胞中，而且在起搏细胞中。实际上，我们将利用多学科技术，包括体内和体外电生理记录，活细胞成像和分子建模，以通过不同的ACS的不同同型ACS来确定Ca2+通道的亚细胞调节。我们提出的研究将扩大我们对特定亚细胞定位和个体调节的理解 Ca2+通道及其如何坐标以介导体内正常心律。了解心脏中Ca2+通道的分子和亚细胞调节将为治疗心律不齐以及SA和AV节点功能障碍的新的，更机械的方法奠定基础，这是我们退伍军人人群中遇到的常见问题。