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Dysregulation of cardiac signaling in disease and stress

疾病和压力下心脏信号传导失调

基本信息

批准号：
10597114
负责人：
Priscila Sato
金额：
$ 41.4万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10597114
关键词：
Adult Affect Amplifiers CASP3 gene Cardiac Cardiac Myocytes Catecholamines Cell Death Cell Death Induction Cell Death Signaling Process Cell Line Cell Survival Cell membrane Cell physiology Cellular Stress Chronic Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Cytosol Decarboxylation Development Disease Disease Progression Enzymes Functional disorder G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein Signaling Pathway G-Protein-Coupled Receptors Glucose Goals Heart Heart Diseases Heart Hypertrophy Heart Injuries Heart failure Hypertension Hypertrophy Hypoxia Ischemia Knock-in Mouse Knock-out Knockout Mice Length Link Lytic Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolic Metabolic syndrome Metabolism Mitochondria Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Outcome Oxidative Phosphorylation Pathologic Pathology Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacological Treatment Phosphorylation Phosphorylation Inhibition Physiological Play Post-Translational Protein Processing Proteins Pyruvate Regulation Reperfusion Injury Reporting Research Resolution Role SLC25A4 gene Signal Transduction Signaling Molecule Stress Testing Treatment Failure Work aorta constriction desensitization design experimental study glucose metabolism heart damage heart metabolism inhibitor innovation mitochondrial creatine kinase mitochondrial metabolism mouse model novel optogenetics oxidation p38 Mitogen Activated Protein Kinase pharmacologic pyruvate dehydrogenase receptor recycling response response to injury

项目摘要

Project Summary G-protein coupled receptor (GPCR) kinase-2 (GRK2) is a key regulator of GPCR recycling and desensitization that is upregulated in several cardiac pathologies, including hypertrophy and heart failure (HF). Cardiac ischemia-reperfusion injury induces ERK-mediated phosphorylation of GRK2 at S670, which results in the translocation of GRK2 from the cytosol to mitochondria. We discovered that in the adult cardiomyocyte mitochondrial GRK2 regulates glucose-mediated oxidative phosphorylation by inhibiting pyruvate dehydrogenase, the rate limiting enzyme of glucose oxidation. Although the physiological impact of mitochondrial GRK2 was reported, it remains largely unknown how mitochondrial GRK2 regulates cardiac mitochondrial metabolism. This proposal focuses on deciphering mechanistically how GRK2 phosphorylation and mitochondrial translocation regulate cardiac glucose metabolism. Additionally, we propose that mitochondrial GRK2 participates in key metabolic signaling post-myocardial infarction (MI) by acting as an amplifier of pyroptosis- a novel lytic cell death mechanism. Thus, we hypothesize that GRK2 phosphorylation at S670 is paramount for cardiomyocyte responses in consequence of altering metabolic availability and cardiac injury. Using a novel GRK-S670A and two Gasdermin E mouse models, we propose to carry out two specific aims: 1.) Determine how mitoGRK2 regulates cardiac mitochondrial metabolism; 2.) Assess whether phosphorylation of GRK2 at S670 modulates cardiac pyroptotic signaling. Overall, our work will shed light on the role of GRK2 phosphorylation at S670 in cardiomyocytes and how this post-translational modification regulates metabolic signaling and chronic-injury responses. The overarching goal of this research is to exploit novel mechanistic signaling for the development and identification of new pharmaceutical drugs for HF treatment.

项目摘要 G蛋白偶联受体（GPCR）激酶2（GRK 2）是GPCR再循环和脱敏的关键调节因子在包括肥大和心力衰竭（HF）在内的几种心脏病中上调。心脏缺血-再灌注损伤诱导ERK介导的GRK 2在S670磷酸化，这导致 GRK 2从细胞质到线粒体的易位。我们发现在成年心肌细胞中线粒体GRK 2通过抑制丙酮酸调节葡萄糖介导的氧化磷酸化脱氢酶是葡萄糖氧化的限速酶。虽然线粒体的生理影响 GRK 2的报道，但线粒体GRK 2如何调节心脏线粒体新陈代谢.这项提案的重点是从机制上破译GRK 2磷酸化和线粒体转位调节心脏葡萄糖代谢。此外，我们认为线粒体 GRK 2通过作为心肌梗死（MI）后代谢信号的放大器参与关键代谢信号传导。 pyroptosis-一种新的裂解性细胞死亡机制。因此，我们假设GRK 2在S670的磷酸化是一个可能的机制。由于代谢可用性改变和心脏损伤，对于心肌细胞反应至关重要。使用新型GRK-S670 A和两种Gasdermin E小鼠模型，我们提出了两个具体目标：1. 确定mitoGRK 2如何调节心脏线粒体代谢; 2.）评估是否磷酸化 S670处的GRK 2调节心脏火旺信号传导。总的来说，我们的工作将阐明GRK 2的作用，心肌细胞中S670的磷酸化以及这种翻译后修饰如何调节代谢信号传导和慢性损伤反应。这项研究的总体目标是利用新的机制，用于HF治疗的新药物的开发和鉴定的信号传导。