Ca and InsP3 Receptor Signaling in Cardiac Myocytes

心肌细胞中的 Ca 和 InsP3 受体信号传导

• 批准号: 8207381
• 负责人: LOTHAR A BLATTER
• 金额: $ 42.59万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8207381
• 关键词: Adult; Affect; Arrhythmia; Atrial Fibrillation; Buffers; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Cell Nucleus; Cells; Complex; Coupling; Development; Disease; Failure; Gene Transfer; Generations; Genetic Transcription; Goals; Health; Hearing; Heart; Heart Atrium; Heart Diseases; Heart Hypertrophy; Heart failure; Homeostasis; Hydrogenase; Hypertrophy; Image; Inositol; Instruction; Laser Scanning Confocal Microscopy; Lead; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Morbidity - disease rate; Muscle Cells; Nitric Oxide; Nitric Oxide Synthase; Noise; Nuclear; Nuclear Export; Oryctolagus cuniculus; Oxidation-Reduction; Permeability; Play; Process; Production; Protein Isoforms; Receptor Signaling; Regulation; Research; Resolution; Rest; Role; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Second Messenger Systems; Signal Pathway; Signal Transduction; Source; Techniques; Testing; Tissues; Transgenic Mice; Ventricular; Wild Type Mouse; calmodulin-dependent protein kinase II; controlled release; cost; heart function; induced pluripotent stem cell; mitochondrial permeability transition pore; mortality; mouse model; photolysis; receptor; receptor function; research study; response; second messenger; transcription factor; transcription factor NF-AT c3; tripolyphosphate; uptake; voltage

PROJECT SUMMARY (See instructions): IPaR-dependent Ca release plays an important role for a wide variety of cardiac functions, including modulation of excitation-contraction coupling (ECC), generation of arrhythmia, modulation of mitochondrial function and regulation of Ca-dependent transcription factors in hypertrophy and hear failure. The overall goal of the proposed study is to 1) identify the mechanisms of IPsR-dependent Ca signaling for diastolic and systolic function, 2) determine the relationship between IPaR-dependent Ca release, mitochondrial Ca uptake and its effect on mitochondrial function, and 3) define the Ca-dependent mechanisms of isoform- and tissuespecific regulation of the hypertrophy transcription factor NFAT. The specific aims are: 1) test the hypothesis that IP3 receptor (IP3R)-dependent Ca release modulates diastolic (SR Ca leak) and systolic (positive inotropic and proarrhythmic effects) Ca signaling in normal adult myocytes and in cardiac hypertrophy and heart failure; 2) test the hypothesis that IPsR-dependent Ca release enhances mitochondrial Ca uptake and mitochondrial Ca-dependent functions (Ca-dependent hydrogenases and metabolic function; opening of the permeability transition pore; nitric oxide (NO) and ROS production by mitochondrial NOS, leading to altered cellular redox state); 3) identify Ca signaling pathways relevant for the activation of the transcription factor NFAT that initiates hypertrophic remodeling processes, and test the hypothesis that Ca-dependent regulation of NFAT is isoform- (NFATcl vs. NFATc3), tissue- (atrial vs. ventricle) and disease state- (normal vs. heart failure) specific and modulated by the redox state of the cell. To achieve these aims a multitude of experimental techniques will be used: high resolution imaging by laser scanning confocal microscopy in single myocytes to measure whole cell and subcellular [Ca]i, [Cajmito and [Ca]sR, whole-cell voltage and current clamp techniques, subcellular photolysis of caged Ca, adenoviral gene-transfer, and pharmacological manipulation of Ca transport and buffering. Experiments will be conducted on adult myocytes from wild-type mouse and rabbit, heart failure rabbit, and transgenic mouse models. The proposed research will provide fundamental new information on the cellular mechanism of Ca signaling relevant to the understanding of cardiac hypertrophy and failure.

项目概述（见说明）：