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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：
7501484
负责人：
BRADLEY K MCCONNELL
金额：
$ 38.28万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2008-07-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7501484
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 Disruption Dobutamine Dose Echocardiography Elevation 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 Rate Rattus Regulation Relaxation Research Research Personnel RyR2 Ryanodine Receptor Calcium Release Channel 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 day density desensitization falls genetic regulatory protein hemodynamics improved in vivo indexing inhibitor/antagonist mouse model myosin-binding protein C novel novel therapeutics 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：心脏病是美国的主要死因。?-肾上腺素能受体（？AR）刺激是增加心脏收缩力的主要机制。然而，慢性交感神经刺激，如发生在心力衰竭（HF），导致受体脱敏和收缩性降低。?- AR刺激信号通过PKA依赖性磷酸化，部分通过PKA结合A-激酶锚定蛋白（AKAP）影响Ca 2+稳态。AKAP靶向特定的细胞内位置，导致PKA与其底物的定位。因此，预期修饰PKA信号传导的试剂将介导增强的变力性反应。基于在心肌细胞中的观察，（a）腺病毒（Ad）介导的Ht 31表达，一种竞争性调节PKA亚基（RII）结合肽，破坏PKA与AKAP的锚定，从而增加对？AR刺激和这（B）令人惊讶地在不存在增加的Ca 2+瞬变的情况下发生。我们渴望测试这个项目的中心假设，即在体内心脏中PKA与AKAP结合的破坏，增强了对？在正常心脏中刺激AR并挽救HF模型中受损的收缩反应。我认为这种增强的变力反应部分是通过增加肌丝Ca 2+敏感性介导的。我们的目标是了解AKAP功能和PKA信号的多组分调节剂在健康和心血管疾病中的信号转导。通过使用Ad介导的Ht 31肽表达通过在体内基因转移的大鼠心脏破坏PKA/AKAP相互作用，我们将评估心脏收缩力和心肌重塑是否增加在正常和失败的大鼠心脏（目的1）;以及是否介导的事件改变收缩力的结果从减少PKA依赖性磷酸化导致肌丝Ca 2+敏感性增加（目的2）。通过使用gravin（AKAP 12）基因敲除小鼠特异性靶向和破坏PKA定位到？2-AR，我们将确定是否心脏功能在体内，增加了阻断AKAP 12调节受体脱敏，类似于观察到的？ARKct在HF中恢复心脏功能的能力（目标3）;以及是否增加心脏功能？AR刺激介导的增加？2-AR依赖性介导的信号传导，使用来自这些小鼠的心脏和肌细胞（目的4）。我们的目标的实现，不仅应该提高我们对PKA信号传导的中枢调节器的功能和信号转导的理解，而且可能代表HF患者变力治疗的新的治疗靶点。