Mechanisms and Therapeutic Role of C-terminus of Cav1.3 L-type Calcium Channel in the Heart

Cav1.3 L型钙通道C末端对心脏的作用机制及治疗作用

• 批准号: 10481142
• 负责人: Mohamed Boutjdir
• 金额: --
• 依托单位: VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481142
• 关键词: Action Potentials; Adult; Aging; Anterior Descending Coronary Artery; Biochemical; Calcium; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular Diseases; Cause of Death; Cell Nucleus; Cell membrane; Cell physiology; ChIP-seq; Coupling; Data; Developed Countries; Development; Echocardiography; Electrophysiology (science); Elements; Enhancers; Environment; FDA approved; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Health; Heart; Heart Atrium; Heart Contractilities; Heart failure; Histology; Ions; Knockout Mice; L-Type Calcium Channels; Laboratories; Left; Left Ventricular Ejection Fraction; Left Ventricular Function; Ligation; Light; Mediating; Messenger RNA; Mus; Muscle Cells; Neonatal; Neurosecretory Systems; Optics; Patients; Peptides; Play; Population; Promoter Regions; Property; Proteins; Public Health; Publishing; Regulation; Reporting; Research; Role; Signal Transduction; Sinoatrial Node; Testing; Therapeutic; Time; Tissues; Ventricular; Veterans; Western Blotting; Work; atrioventricular node; density; design; design and construction; differential expression; fetal; functional restoration; gene therapy; heart function; improved; in vivo; innovation; mouse model; novel; novel therapeutic intervention; patch clamp; promoter; rational design; transcription factor; transcriptome sequencing; translational impact; vector; voltage

In the heart, there are two types of L-type calcium channels, the classical Cav1.2 and the novel less characterized Cav1.3. They both convert cell-membrane depolarization into calcium transients and initiate excitation-contraction coupling. Interestingly, Cav1.3 is expressed in the supraventricular tissue and ventricles of the fetal and neonatal hearts but not in the ventricles of the adult heart. Cav1.3 also has an extended C-terminus. Relevant to this application is that our preliminary data demonstrate that the C-terminus of Cav1.3 is mobile and functions as a transcription auto-enhancer of its own Cav1.3 gene. This unique endogenous property can be leveraged to generate inotropic force necessary to restore cardiac function in the setting of heart failure which is highly prevalent in Veterans. Here we will test, for the first time, the hypothesis that the translocation of the Cav1.3 C-terminus mobile fragment to the nucleus will upregulate Cav1.3 gene expression at specific promoter region(s) and thus provide additional calcium entry into the cardiac myocyte resulting in improved cardiac function in a murine model of heart failure. This hypothesis will be tested in three aims: Aim 1: Investigate the regulation of gene expression by C-terminus of Cav1.3 in a native environment; Aim 2: Determine the mechanisms of Cav1.3 C-terminus regulation of Cav1.3 gene promoter activity; Aim 3: Investigate the potential therapeutic impact of Cav1.3 C-terminus in heart failure. Studies will be carried out by a combination of electrophysiological (patch-clamp and optical mapping), RNA-seq, biochemical, echocardiography and histology, in in-vivo and ex-vivo hearts. The findings from this work will provide a novel mechanism by which Cav1.3 L-type calcium channel acts not only as a conventional ion pore but also as a transcription factor regulating gene expression and cell function via its C-terminus. The ability of the C-terminus of Cav1.3 to upregulate its own gene can be exploited for the development of novel inotropic therapies for heart failure which is prevalent in Veterans.

在心脏中，l型钙通道有两种，经典的Cav1.2型和新颖的Cav1.2型