Mechanisms of Maladaptation in Heart Failure

心力衰竭适应不良的机制

基本信息

批准号：
8959445
负责人：
Howard A Rockman
金额：
$ 39.75万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8959445
关键词：
ADRBK1 gene Adopted Affect Affinity Chromatography Agonist Arrestins Bar Codes Cardiac Cardiac Myocytes Cells Coupled Data Development Endothelial Cells Equilibrium Fibroblasts Funding G Protein-Coupled Receptor Genes G Protein-Coupled Receptor Signaling GRK5 gene GTP-Binding Proteins Grant Growth Health Heart Heart failure Hybrids Immigration In Vitro Injury Isoproterenol Lead Ligands Lung Mass Spectrum Analysis Mediating Molecular Molecular Conformation Mus Outcome Pathway interactions Pattern Pertussis Toxin Phosphorylation Phosphorylation Site Phosphotransferases RNA Recruitment Activity Ribosomes Role Signal Pathway Signal Transduction Site Stress Tail Translating Work base cadherin 5 carvedilol cell type coronary fibrosis desensitization in vivo injured insight novel novel therapeutics receptor response response to injury translational study

项目摘要

DESCRIPTION (provided by applicant): ß-arrestins were initially discovered to desensitize GPCR signaling in response to agonist stimulation. However, it is now appreciated that ß-arrestins can also transduce multiple effector pathways independent of G-protein signaling when receptors are stimulated by certain ligands, a concept known as biased signaling. The proposed mechanism for this signaling bias is based on the "barcode" hypothesis where unbiased and ß-arrestin-biased ligands impart distinct patterns of receptor phosphorylation by specific GPCR kinases (GRKs), thus converting a distinct ligand stabilized receptor conformation into selective ß-arrestin function and downstream signaling. In this proposal we plan to discover new mechanistic insights for the precise molecular details that underlie ß-arrestin biased signaling and determine how this may influence cardiac function. We will use a mass spectrometry phosphoproteomic based approach to determine whether Carvedilol induces a unique phosphorylation bar code of the ß1AR compared to the balance agonist isoproterenol, and will translate these findings in vivo by using mice conditionally lacking ß-arrestin in differnt cell types of the heart and determine the effect of ß-arrestin bias on the transcriptional signatue and cardiac function under normal and injured conditions. We propose the following specific aims: Aim 1: Determine the specific phosphorylation "bar code" on the c-terminal tail of ß1AR responsible for Gαi dependent ß-arrestin-biased signaling. Aim 2: Determine the mechanism of ß1AR-biased signaling in cardiac fibroblasts. Aim 3: Determine the cardiac cell type responsible for ß-arrestin signaling that promotes cardiac fibrosis in response to injury. Aim 4: Determine th cell-type specific RNA signature of wild type and conditionally deleted ß-arrestin1 and 2 KO mice in response to the biased ligand carvedilol and after cardiac injury.

描述（由适用提供）：最初发现β-arrestin是为了响应激动剂刺激而脱敏的GPCR信号传导。然而，现在人们认为，当某些配体刺激受体时，ß-arrestin还可以转移多个效应器途径，而不是G蛋白信号传导，该概念被称为偏置信号传导。这种信号偏置的提出机制基于“条形码”假设，在该假说中，无偏见的和β-arrestin偏置的配体通过特定的GPCR激酶（GRKS）赋予受体磷酸化的不同模式，从而将独特的配体稳定受体构型转化为选择性的coptive-s稳定受体构型转化为选择性的ß-甲rardrestin信号和下链信号。在此提案中，我们计划发现新的机械洞察力，以确切的分子细节，这些细节是基于信号传导的基础，并确定这可能如何影响心脏功能。 We will use a mass Spectrometry phosphoproteomic based approach to determine whether Carvedilol induces a unique phosphorylation bar code of the ß1AR compared to the balance agonist isoproterenol, and will translate these findings in vivo by using mice conditionally lacking ß-arrestin in different cell types of the heart and determine the effect of ß-arrestin bias on the transcriptional signatue and cardiac function under normal and injured 状况。我们提出以下特定目的：目标1：确定目标2：确定心脏成纤维细胞中ß1AR偏置信号的机理。 AIM 3：确定负责β-arrestin信号传导的心脏细胞类型，该信号促进损伤的心脏纤维化。 AIM 4：根据有偏见的配体卡维丝酚和心脏损伤后，确定野生型的细胞类型特异性RNA特异性RNA特异性RNA特异性和有条件删除的ß-arrestin1和2 KO小鼠。