Targeted Disruption of Beta-Adrenergic Signaling to Increase Cardiac Contractilit

有针对性地破坏 β-肾上腺素能信号以增加心脏收缩力

基本信息

批准号：
7800355
负责人：
BRADLEY K MCCONNELL
金额：
$ 42.07万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-03 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7800355
关键词：
A kinase anchoring protein AKAP12 gene AKAP13 gene Achievement Acute Adenoviruses Adrenergic Agents Adrenergic Receptor Adverse effects Agonist Apoptosis Arrhythmia Back Binding Binding Sites CREB1 gene Calcium Calcium Signaling Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Caspase Catheterization Cause of Death Cell physiology Cells Chronic Clinical Complex Congenital Heart Defects Coronary Arteriosclerosis Cyclic AMP Cyclic AMP-Dependent Protein Kinases Depressed mood Development Diagnosis Dimensions Disease Dobutamine Dose Echocardiography Evaluation Event Functional disorder Gene Expression Gene Expression Microarray Analysis Gene Transfer Goals Gravin Health Heart Heart Diseases Heart failure Homeostasis Human Hypertension Image Impairment Infusion procedures Isoproterenol Knock-out Knockout Mice Lead Left Ventricular Ejection Fraction Location Measures Mediating Microfilaments Milrinone Modeling Morphology Mus Muscle Cells Myocardial Myocardial Infarction Myocarditis Patients Peptides Phosphodiesterase Inhibitors Phosphorylation Principal Investigator Public Health Publishing Rattus Regulation Relaxation Research Research Personnel RyR2 Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Signal Pathway Signal Transduction Syndrome Tachycardia Testing Thyroid Diseases Tissues Troponin I United States Ventricular Ventricular Arrhythmia Ventricular Remodeling adenoviral-mediated adenylyl cyclase 2 adrenergic base blood pump density desensitization falls genetic regulatory protein hemodynamics improved in vivo indexing inhibitor/antagonist mouse model myosin-binding protein C new therapeutic target novel papillary muscle phospholamban pressure programs protein function receptor response therapeutic target

项目摘要

DESCRIPTION: Heart disease is the leading cause of death in the USA. ?-adrenergic receptor (?-AR) stimulation is the primary mechanism to increase cardiac contractility. However chronic sympathetic stimulation, as occurs in heart failure (HF), results in receptor desensitization and reduced contractility. ?-AR stimulation signals through PKA-dependent phosphorylation in part by PKA binding to A-kinase anchoring proteins (AKAPs) to influence Ca2+ homeostasis. AKAPs are targeted to specific intracellular locations resulting in localization of PKA with its substrates. Thus agents that modify PKA signaling would be expected to mediate an enhanced inotropic response. Based on observations in myocytes that (a) adenoviral (Ad) mediated Ht31 expression, a competing regulatory PKA subunit (Rll) binding peptide, disrupted PKA anchoring to AKAPs which increased the contractile response to ?-AR stimulation and this (b) surprisingly occurred in the absence of increased Ca2+ transients. We are eager to test the central hypothesis of this project that disruption of PKA binding to AKAPs in hearts in vivo, enhances the contractile response to ?-AR stimulation in normal hearts and rescues the impaired contractile response a model of HF. I propose that this increased inotropic response is mediated in part by increasing myofilament Ca2+ sensitivity. Our goal is to understand AKAP function and the signal transduction of this multi-component regulator of PKA signaling in health and in cardiovascular disease. By using Ad-mediated Ht31 peptide expression via in vivo gene transfer of rat hearts to disrupt PKA/AKAP interactions, we will evaluate whether cardiac contractility and myocardial remodeling are increased in both normal and failing rat hearts (Aim 1); and whether the events mediating altered contractility results from decreased PKA-dependent phosphorylation leading to increased myofilament Ca2+ sensitivity (Aim 2). By using gravin (AKAP12) knockout mice to specifically target and disrupt PKA localization to the ?2- AR, we will determine whether cardiac function in vivo, is increased by blocking AKAP12 regulated receptor desensitization, similar to that observed with ?ARKct's ability to restore cardiac function in HF (Aim 3); and whether increased cardiac function following ?-AR stimulation is mediated by increased ?2-AR dependent mediated signaling, using hearts and myocytes from these mice (Aim 4). Achievement of our aims, should not only improve our understanding of the function and signal transduction for this central regulator of PKA signaling, but may potentially represent a novel therapeutic target for inotropic therapy for patients with HF.

描述：心脏病是美国死亡的主要原因。？ - 肾上腺素受体（？-AR）刺激是增加心脏收缩力的主要机制。然而，如心力衰竭（HF）发生的慢性交感神经刺激导致受体脱敏和收缩力降低。？ - 通过PKA与A-激酶锚定蛋白（AKAP）结合的部分通过PKA依赖性磷酸化的刺激信号，以影响Ca2+稳态。 AKAP针对特定的细胞内位置，导致PKA与其底物定位。因此，预期修改PKA信号传导的药物将介导增强的肌力反应。基于在心肌细胞中的观察结果，即（a）腺病毒（AD）介导的HT31表达，一种竞争性的调节性PKA亚基（RLL）结合肽，锚定在AKAP上的PKA破坏了AKAP，从而增加了收缩对？-AR刺激的反应？-AR刺激，这（b）出现了（b）在没有增加CA2+瞬态的情况下会增加。我们渴望测试该项目的中心假设，即PKA与体内心脏中AKAP的结合破坏，从而增强了对正常心脏刺激的收缩反应，并挽救了受损的收缩反应HF的模型。我建议，这种增加的肌力反应部分是通过增加肌丝Ca2+敏感性来介导的。我们的目标是了解AKAP功能以及该多组分调节剂在健康和心血管疾病中的信号转导。通过通过大鼠心脏的体内基因转移来破坏PKA/AKAP相互作用，使用AD介导的HT31肽表达，我们将评估正常和失败的大鼠心脏中心脏收缩和心肌重塑是否增加（AIM 1）；以及导致收缩性改变的事件是否导致PKA依赖性磷酸化降低导致肌丝Ca2+敏感性升高（AIM 2）。通过使用Gravin（AKAP12）敲除小鼠特异性靶向并破坏PKA定位到？2AR，我们将通过阻止AKAP12调节受体脱敏的体内心脏功能是否可以增加体内的心脏功能，类似于与？ARKCT在HF中还原心脏功能的能力相似（AIM 3）；以及使用这些小鼠的心脏和心肌细胞增加的刺激后心功能增加？AR刺激是否介导？2-AR刺激（AIM 4）。实现我们的目标，不仅应该改善我们对PKA信号传导调节剂功能和信号转导的理解，而且还可能代表了针对HF患者的肌瘤治疗的新型治疗靶标。