Cross-talk with the Insulin Receptor Attenuates Adrenergic Function within the He

与胰岛素受体的串扰减弱了He内的肾上腺素能功能

基本信息

批准号：
8267259
负责人：
David Cervantes
金额：
$ 4.72万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2014-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267259
关键词：
A kinase anchoring protein Accounting Acute Adrenergic Agents Adrenergic Receptor Affect Animals Attenuated Biological Models Cardiac Cardiac Myocytes Cardiomyopathies Catecholamines Cell membrane Chronic Complex Coronary Arteriosclerosis Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytosol Data Depressed mood Diabetes Mellitus Diffusion Disease Down-Regulation Epidemic Fluorescence Resonance Energy Transfer Functional disorder Genes Heart Heart failure Hyperinsulinism Hypertension Imaging Techniques Impairment In Vitro Insulin Insulin Receptor Isoproterenol Measurement Mediating Modeling Molecular Mus Muscle Cells Myocardium Non-Insulin-Dependent Diabetes Mellitus Performance Perfusion Pertussis Toxin Phosphorylation Physiological Population Protein Isoforms Proteins Receptor Activation Receptor Cross-Talk Recombinants Rest Risk Factors Signal Transduction Signaling Protein Time Work adenoviral-mediated adrenergic base cellular imaging desensitization diabetic cardiomyopathy diabetic patient in vivo inhibitor/antagonist insulin signaling mutant novel therapeutics phosphodiesterase IV phospholamban prevent receptor response trafficking

项目摘要

DESCRIPTION (provided by applicant): Diabetes Mellitus is a growing epidemic, affecting 8% percent of population in the US. Type 2 diabetes mellitus, accounting for 90-95% of diabetes cases, is a well characterized risk factor for cardiomyopathy and heart failure. Diabetic Cardiomyopathy (DCM) is characterized by both systolic and diastolic dysfunction, resulting in decreased cardiac function, in the absence of coronary artery disease (CAD) and hypertension. Interestingly, DCM is associated with hyperinsulinemia and depressed adrenergic signaling leading to decreased contractility despite elevated catecholamine levels. The lack of CAD and hypertension in DCM, even in the presence of elevated catecholamines, suggests that hyperinsulinemia elicits direct cardiomyocyte insult, possibly by modulating adrenergic function. The consequence of concomitant insulin receptor (IR) and adrenergic receptor (AR) stimulation within the heart, however, remains unknown. Here, our major hypothesis is that insulin signaling attenuates the 2AR-induced elevation in cardiac performance in response to elevated catecholamines. Our preliminary data show that chronic insulin treatment impairs 2AR stimulation of cAMP/protein kinase A (PKA) signaling, PKA phosphorylation of phospholamban (PLN), and myocyte contraction rate response in cardiac myocytes. This inhibitory effect is mediated by both enhanced 2AR/Gi coupling and an increased expression of phosphodiesterase 4 (PDE4); together these contribute to a down-regulation of 2AR-induced cAMP signaling. The signaling mechanism underlying the cross-talk between IRs and 2ARs, as well as the physiological consequence, in the myocardium remains unknown. We hypothesize that decreased cardiac performance observed in DCM results, in part, from chronic insulin stimulation which impairs 2AR signaling via increased 2AR/Gi coupling and increased PDE4 expression. By combining our well-established model system based on myocytes isolated from 2AR gene deficient mice with our newly-developed FRET-based cell imaging techniques to analyze the dynamics of cAMP/PKA activities, we will determine the mechanism and consequence of 2AR/IR cross-talk in cardiomyocytes. The combination of functional myocyte contraction measurements and real-time measurement of 2AR-induced cAMP/PKA activities with recombinant adenoviral-mediated delivery of mutant signaling components allows for a unique yet powerful approach to uncover the mechanism underlying the functional integration of the insulin and 2AR signaling network. By elucidating the mechanism by which insulin attenuates adrenergic-mediated cardiac contractility both in vitro and in vivo, new therapeutic strategies may be developed to treat diabetic patients with heart failure.

描述（由申请人提供）：糖尿病是一种日益严重的流行病，影响着美国 8% 的人口。 2 型糖尿病占糖尿病病例的 90-95%，是心肌病和心力衰竭的明确危险因素。糖尿病心肌病 (DCM) 的特点是收缩和舒张功能障碍，导致心功能下降，但没有冠状动脉疾病 (CAD) 和高血压。有趣的是，DCM 与高胰岛素血症和肾上腺素信号传导抑制相关，尽管儿茶酚胺水平升高，但导致收缩力下降。 DCM 中缺乏 CAD 和高血压，即使存在升高的儿茶酚胺，这表明高胰岛素血症可能通过调节肾上腺素能功能而引起直接心肌细胞损伤。然而，心脏内胰岛素受体（IR）和肾上腺素能受体（AR）同时刺激的后果仍然未知。在这里，我们的主要假设是，胰岛素信号传导减弱了 2AR 诱导的儿茶酚胺升高引起的心脏功能升高。我们的初步数据表明，长期胰岛素治疗会损害 cAMP/蛋白激酶 A (PKA) 信号传导的 2AR 刺激、受磷蛋白 (PLN) 的 PKA 磷酸化以及心肌细胞中的肌细胞收缩率反应。这种抑制作用是由 2AR/Gi 偶联增强和磷酸二酯酶 4 (PDE4) 表达增加介导的；这些共同导致 2AR 诱导的 cAMP 信号传导下调。心肌中 IR 和 2AR 之间串扰的信号传导机制以及生理后果仍然未知。我们假设 DCM 中观察到的心脏功能下降部分是由于慢性胰岛素刺激，通过增加 2AR/Gi 偶联和增加 PDE4 表达来损害 2AR 信号传导。通过将我们完善的基于 2AR 基因缺陷小鼠心肌细胞分离的模型系统与我们新开发的基于 FRET 的细胞成像技术相结合来分析 cAMP/PKA 活性的动态，我们将确定 2AR/IR 交叉的机制和结果-心肌细胞中的对话。功能性肌细胞收缩测量和实时测量 2AR 诱导的 cAMP/PKA 活性与重组腺病毒介导的突变信号成分的传递相结合，可以采用独特而强大的方法来揭示胰岛素和 2AR 功能整合的机制信令网络。通过阐明胰岛素在体外和体内减弱肾上腺素介导的心肌收缩力的机制，可以开发新的治疗策略来治疗患有心力衰竭的糖尿病患者。