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Molecular Regulation of cardiac adrenergic signaling

心脏肾上腺素信号传导的分子调节

基本信息

批准号：
10425249
负责人：
YANG K XIANG
金额：
$ 43.54万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10425249
关键词：
A kinase anchoring protein Adrenergic Agents Adrenergic Receptor Agonist Apoptosis Arrhythmia Attenuated Binding C-terminal Calcium Cardiac Cardiac Myocytes Cardiotoxicity Chronic Complex Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases DLG1 gene Data Development Disease Dissociation Ensure Exposure to Functional disorder GRK5 gene GTP-Binding Proteins Heart Heart Contractilities Heart failure Hypertrophy Isoproterenol L-Type Calcium Channels Link Modeling Molecular Mus Muscle Cells Orphan Perfusion Periodicity Pharmacology Phosphorylation Phosphotransferases Physiological Physiology Play Production Regulation Role Sarcoplasmic Reticulum Scaffolding Protein Serine Signal Transduction Stress Testing Transgenes Transgenic Mice Transgenic Organisms Treatment Failure beta-adrenergic receptor biological adaptation to stress calmodulin-dependent protein kinase II constriction cytotoxicity genetic predictors heart function insight mouse model mutant novel phosphoric diester hydrolase preservation pressure receptor response scaffold therapeutic target tool

项目摘要

Summary β adrenergic receptors (βARs) are critical for cardiac function and are linked to HF. Chronic β1AR-cAMP signaling promotes activation of CaMKII, which is requisite for all the detrimental effects during maladaptive remodeling in heart. However, the mechanism governing this specific signaling regulation by β1AR in HF development is still incompletely understood. We aim to reveal a novel supercomplex of cardiac beta1 adrenergic receptor that is orchestrated by scaffold protein SAP97 and connects to L-type calcium channel directly. Moreover, SAP97 also scaffold AKAP79/PKA and PDE4D8 in the complex to ensure rapid and robust regulation of L-type calcium channel in local vicinity, which is essential to maintain rhythmic beat-to- to-beat cardiac contraction during stress response. We aim to gain insight of regulation of this sophisticated beta1 adrenergic receptor supercomplex in spatially differentiated cardiac myocytes and explore the dissemble and dysfunction of this complex in disease development via promoting cytotoxicity in heart. We hypothesize that GRK5 acts as a molecular switch to turn on Epac-dependent activation of CaMKII. We have generated mice to simulate dissociation of the b1AR-SAP97 complex and to study SAP97-dependent b1AR signaling in physiology and diseases. This study will provide new insight governing the specific b1AR signaling involved in physiology an in HF, and offer GRK5 as a complementary therapeutic target for HF. The hypothesis will be examined in the following aims: Aim 1. A SAP97 complex facilitates PKA-dependent regulation of EC coupling. Aim 2. Disruption of b1AR-SAP97 interaction promotes b1AR-induced CaMKII activity. Aim 3. GRK5 phosphorylation of b1AR at S475 controls the binding of b1AR to SAP97 to gate cardiotoxic CaMKII in HF.

总结 β肾上腺素能受体（β AR）对心脏功能至关重要，并与HF相关。慢性β1AR-cAMP 信号传导促进CaMKII的激活，这是适应不良期间所有有害作用所必需的。心脏重塑然而，β 1 AR在HF中的这种特异性信号调节机制，发展仍然不完全清楚。我们的目标是揭示一种新的心脏β 1超复合物由支架蛋白SAP 97协调并连接到L型钙通道的肾上腺素能受体直接.此外，SAP 97还在复合物中支架化AKAP 79/PKA和PDE 4D 8，以确保快速和有效地结合。在局部附近的L型钙通道的强大调节，这是维持节律性搏动所必需的，在应激反应中的心脏收缩。我们的目标是深入了解这种复杂的监管 β 1肾上腺素能受体超复合物在空间分化的心肌细胞，并探讨通过促进心脏的细胞毒性，这种复合物在疾病发展中的分解和功能障碍。我们假设GRK 5作为分子开关开启Epac依赖的CaMK II激活。我们已经产生了小鼠来模拟b1 AR-SAP 97复合物的解离，并研究SAP 97依赖性 b1 AR信号在生理学和疾病中的作用。这项研究将提供新的见解，管理特定的b1 AR 参与生理学和HF中的信号传导，并提供GRK 5作为HF的补充治疗靶点。该假设将在以下目标中进行检验：目标1。SAP 97复合物促进PKA依赖性调节EC偶联。目标2.破坏b1 AR-SAP 97相互作用促进b1 AR诱导的CaMKII 活动目标3。GRK 5在S475处磷酸化b1 AR控制b1 AR与SAP 97的结合，以门控心脏毒性CaMKII。