Molecular Regulation of cardiac adrenergic signaling
Molecular Regulation of cardiac adrenergic signaling
批准号:
10155584
负责人:
YANG K XIANG
金额:
$43.54万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-05-01 至 2023-04-30
关键词:
A kinase anchoring proteinAdrenergic AgentsAdrenergic ReceptorAgonistApoptosisArrhythmiaAttenuatedBindingC-terminalCalciumCardiacCardiac MyocytesCardiotoxicityChronicComplexCouplingCyclic AMPCyclic AMP-Dependent Protein KinasesDLG1 geneDataDevelopmentDiseaseDissociationEnsureExposure toFunctional disorderGRK5 geneGTP-Binding ProteinsHeartHeart ContractilitiesHeart failureHypertrophyIsoproterenolL-Type Calcium ChannelsLinkModelingMolecularMusMuscle CellsOrphanPerfusionPeriodicityPharmacologyPhosphorylationPhosphotransferasesPhysiologicalPhysiologyPlayProductionRegulationRoleSarcoplasmic ReticulumScaffolding ProteinSerineSignal TransductionStressTestingTransgenesTransgenic MiceTransgenic OrganismsTreatment Failurebeta-adrenergic receptorbiological adaptation to stresscalmodulin-dependent protein kinase IIconstrictioncytotoxicitygenetic predictorsheart functioninsightmouse modelmutantnovelphosphoric diester hydrolasepreservationpressurereceptorresponsescaffoldtherapeutic targettool
中文摘要
摘要
β肾上腺素能受体(βAR)对心功能起关键作用,并与心衰有关。慢性β1AR-cAMP
信号促进CaMKII的激活,这是适应不良期间所有有害影响所必需的
心脏重塑。然而,β1AR在HF中控制这一特定信号调节的机制
人们对发展的理解仍然不完全。我们的目标是揭示一种新的心脏β1超复合体
连接L钙通道的由支架蛋白SAP97调控的肾上腺素能受体
直接去吧。此外,SAP97还在建筑群中搭建了AKAP79/PKA和PDE4D8支架,以确保快速和
局部L型钙通道的强健调节是维持节律性心动过速所必需的
在应激反应中跳动心脏收缩。我们的目标是深入了解这一复杂的
β1肾上腺素能受体超复合体在空间分化的心肌细胞中的表达
通过促进心脏中的细胞毒作用来掩盖和功能这种复合体在疾病发展中的作用。我们
假设GRK5作为分子开关开启EPAC依赖的CaMKII激活。我们
已经建立了小鼠来模拟b1AR-SAP97复合体的解离,并研究SAP97依赖
B1AR信号在生理和疾病中的作用。这项研究将为管理特定的b1AR提供新的见解
参与生理学和心力衰竭的信号转导,并提供GRK5作为心力衰竭的补充治疗靶点。
这一假说将在以下目标中得到验证:目标1.SAP97复合体促进PKA依赖
EC联结的调控。目的2.阻断b1AR-SAP97相互作用促进b1AR诱导的CaMKII
活动。目的3.b1AR在S475处的GRK5磷酸化控制b1AR与SAP97与GATE的结合
心毒性CaMKII在HF中。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
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