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Molecular Mechanisms of Cardiac beta1AR-EGFR Association and Signaling

心脏 β1AR-EGFR 关联和信号转导的分子机制

基本信息

批准号：
8204906
负责人：
Douglas Tilley
金额：
$ 38.25万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204906
关键词：
ADRBK1 gene Address Adrenergic Receptor Apoptosis Apoptotic Binding Cardiac Cardiac Myocytes Catecholamines Cell Culture System Cell Culture Techniques Cell Survival Chronic Complex Data Development EGF gene Energy Transfer Epidermal Growth Factor Receptor G protein coupled receptor kinase GRK5 gene Gene Expression Heart Heart failure Immunoprecipitation Kinetics Knockout Mice Lead Ligands Mass Spectrum Analysis Mediating Modeling Molecular Morbidity - disease rate Mus Myocardial Infarction Neonatal Outcome Pathway interactions Pattern Phosphorylation Preparation Process Protein Isoforms Proteins Proteomics Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Reliance Reporting Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Syndrome Testing Therapeutic Transactivation United States heart preservation improved in vivo in vivo Model insight mortality novel novel therapeutic intervention novel therapeutics radioligand receptor receptor internalization receptor-mediated signaling response therapy development trafficking

项目摘要

Project Summary Heart failure remains one of the most highly prevalent and costly syndromes that leads to morbidity and mortality in the United States and increasingly around the world. ¿1-adrenergic receptor (¿1AR) signaling is critical to the regulation of cardiac function in response to sympathetic input but becomes deleterious in response to chronic catecholamine stimulation during the progression of heart failure. Recently, ¿1AR- mediated transactivation of epidermal growth factor receptor (EGFR) was reported to relay cardioprotection under conditions of chronically elevated catecholamine stimulation, maintaining normal cardiac function and promoting cell survival via reduced apoptosis. The molecular mechanism(s) by which ¿1AR-mediated EGFR transactivation relays cardioprotective signaling are poorly understood and the apoptotic pathways regulated by this process are unknown. Recent evidence showed that ¿1AR and EGFR associate as a receptor complex in a G protein-coupled receptor kinase (GRK)-dependent manner, though the role of specific GRKs in the regulation of ¿1AR-EGFR association is unknown. Further, differential ligand stimulation of the ¿1AR-EGFR complex by catecholamine or EGF was shown to induce divergent receptor complex internalization and trafficking of downstream effectors. While proteomic studies of EGFR signaling have begun to describe protein networks, or signalosomes, assembled in response to EGF stimulation, the EGFR signalosome response to catecholamine-mediated stimulation of the ¿1AR-EGFR complex has not been characterized. Since the molecular regulation of ¿1AR-EGFR association and subsequent intracellular signaling may contribute to beneficial cardiac outcomes during heart failure, characterization of this novel signaling paradigm may lead to an improved therapeutic approach to heart failure. Thus, the aims of this proposal are to: 1) define the role of cardiac GRKs in the regulation of ¿1AR-EGFR association, 2) determine how differential stimulation of the ¿1AR-EGFR complex impacts receptor trafficking and signaling normally and during heart failure, and 3) characterize the impact of catecholamine stimulation of the ¿1AR-EGFR complex on apoptotic signaling and regulation of the EGFR signalosome normally and during heart failure. These aims will be assessed by elucidating the kinetics of ¿1AR-EGFR association, trafficking and downstream signaling responses through the use of fluorescent resonance energy transfer (FRET), immunoprecipitation, radioligand binding, RT-PCR and mass spectroscopy. Regulation of ¿1AR-EGFR association normally and during heart failure will be assessed using neonatal murine cardiomyocytes and whole heart preparations from wild-type and cardiac- specific GRK knockout mice with or without myocardial infarction. These studies will provide novel insight into how the ¿1AR-EGFR complex exerts cardioprotection, identifying key signaling pathways for development of an improved molecular approach to heart failure therapy.

项目总结