CaMKII Regulation of Cardiac Ryanodine Receptors in Atrial Fibrillation

CaMKII 对心房颤动中心脏兰尼定受体的调节

• 批准号: 7837367
• 负责人: Xander H.T. Wehrens
• 金额: $ 20.82万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837367
• 关键词: Affect; Alanine; American; Animal Model; Antibodies; Arrhythmia; Atrial Fibrillation; Backcrossings; Binding; Binding Sites; Biological Assay; Biopsy; Calmodulin; Cardiac; Cardiac Myocytes; Chronic; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Enzymes; FKBP1B gene; Fibrinogen; Figs - dietary; Genetic; Goals; Heart; Heart Atrium; Heart Diseases; Heart Rate; Homeostasis; Human; Image; Inherited; Link; Lipid Bilayers; Measurement; Measures; Mediating; Modeling; Molecular; Mus; Muscle Cells; Mutant Strains Mice; Mutate; Mutation; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Inhibition; Phosphorylation Site; Phosphotransferases; Play; Predisposition; Prevention; Probability; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Reagent; Recombinants; Regulation; Research Personnel; Role; RyR2; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Serine; Sinus; Site; Syndrome; Testing; Ventricular Tachycardia; alanylaspartic acid; calmodulin-dependent protein kinase II; inhibitor/antagonist; mortality; mutant; prevent; programs; response; translational study

DESCRIPTION (provided by applicant): Defects in the regulation of intracellular Ca2+ released from sarcoplasmic reticulum (SR) stores have been demonstrated in inherited arrhythmia syndromes such as catecholaminergic polymorphic ventricular tachycardia (CPVT), but may also provide an arrhythmogenic trigger in acquired arrhythmias like atrial fibrillation (AF). Recent studies have revealed defects in the regulation of ryanodine receptor (RyR2) Ca2+ release channels in patients with AF. AF is the most prevalent arrhythmia, affecting more than 2 million Americans each year and causing a twofold increase in mortality. Since the activity of RyR2 is strongly regulated by Ca2+/calmodulin-dependent kinase (CaMKII), which binds to RyR2 and is activated in response to faster heart rates, it has been proposed that abnormal CaMKII regulation plays/a role in the onset of AF. The long-term goal of this project is to define the cellular/ molecular mechanisms by which abnormal CaMKII phosphorylation of RyR2 at serine 2814 (S2814) leads to AF, by studying human atrial biopsies and genetically-altered mice in which RyR2 activity has been altered, or the CaMKII phosphorylation site on RyR2 has been inactivated. Our hypothesis is that direct binding of CaMKII to RyR2 enables the enzyme to sense and amplify SR Ca2+ leak, which may increase the likelihood of AF in hearts more susceptible to arrhythmias due to an inherited mutation in RyR2 (R176Q) or the absence of the RyR2- stabilizing subunit FKBP12.6. The specific aims are to: 1) Demonstrate that CaMKII phosphorylation at S2814 of RyR2 is increased in human atrial biopsies from patients with AF; 2) Define the molecular mechanisms by which CaMKII regulates RyR2; 3) Determine if CaMKII phosphorylation of RyR2 increases the probability of AF in RyR2-R176Q mutant or FKBP12.6-deficient mice; 4) Determine if prevention of CaMKII phosphorylation of RyR2 in FKBP12.6-deficient mice decreases susceptibility to AF. We propose to conduct translational studies ranging from single channel measurements of RyR2, Ca2+ imaging in isolated cardiomyocytes and arrhythmia-inducibility studies in genetically-altered mice, to elucidate the molecular mechanisms underlying RyR2-dependent initiation of AF. It is anticipated that the results of these studies will advance our understanding of CaMKII-dependent mechanisms underlying the initiation of AF as well as other cardiac arrhythmias associated with abnormal Ca2+ homeostasis. Furthermore, the reagents and animal models developed for this project may be utilized to create new drugs for AF and other common diseases of the heart.

DESCRIPTION (provided by applicant): Defects in the regulation of intracellular Ca2+ released from sarcoplasmic reticulum (SR) stores have been demonstrated in inherited arrhythmia syndromes such as catecholaminergic polymorphic ventricular tachycardia (CPVT), but may also provide an arrhythmogenic trigger in acquired arrhythmias like atrial fibrillation （AF）。最近的研究表明，AF患者的Ryanodine受体（RYR2）CA2+释放通道的调节缺陷。 AF是最普遍的心律失常，每年影响超过200万美国人，并导致死亡率增加两倍。由于RYR2的活性受CA2+/钙调蛋白依赖性激酶（CAMKII）的强烈调节，该激酶（CAMKII）与RYR2结合并因更快的心率而被激活，因此已经提出，异常的CAMKII调节作用/A在AF的发作中起作用/A作用。 该项目的长期目标是定义丝氨酸2814（S2814）在丝氨酸2814（S2814）中对RYR2异常磷酸化的细胞/分子机制，通过研究人类心房活检，并在RyR2活性中研究RyRY2活性的小鼠在RyR2活检中已改变了camkii phoskii phosperiv phospativy2。 Our hypothesis is that direct binding of CaMKII to RyR2 enables the enzyme to sense and amplify SR Ca2+ leak, which may increase the likelihood of AF in hearts more susceptible to arrhythmias due to an inherited mutation in RyR2 (R176Q) or the absence of the RyR2- stabilizing subunit FKBP12.6.具体目的是：1）证明RYR2 S2814处的CAMKII磷酸化在AF患者的人类心房活检中增加了； 2）定义CAMKII调节RYR2的分子机制； 3）确定RYR2的CAMKII磷酸化是否会增加RYR2-R176Q突变体或FKBP12.6缺陷小鼠中AF的概率； 4）确定在FKBP12.6缺乏小鼠中RYR2的CAMKII磷酸化是否会降低对AF的敏感性。 我们建议进行转化研究，从分离的心肌细胞中的RyR2，Ca2+成像的单个通道测量值和心律不齐的小鼠中的心律失常诱导性研究阐明了RYR2依赖于AF AF的RyR2依赖性启动的分子机制。预计这些研究的结果将提高我们对AF启动以及与异常CA2+稳态相关的其他心律不齐的基础机制以及其他心律不齐的理解。此外，为该项目开发的试剂和动物模型可用于为AF和其他常见疾病创建新药。