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：
10436027
负责人：
Priscila Sato
金额：
$ 41.49万
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 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436027
关键词：
Adult Affect Amplifiers CASP3 gene Cardiac Cardiac Myocytes Catecholamines Cell Death Cell Death Signaling Process Cell Line Cell Survival Cell membrane Cell physiology Cells 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-Coupled Receptors GPCR Signaling Pathway Glucose Goals Heart Heart Diseases Heart Hypertrophy Heart Injuries Heart failure Hypertension Hypertrophy Hypoxia Knock-in Mouse Knock-out Knockout Mice Length Light 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 Pharmacology Phosphorylation Phosphotransferases Physiological Play Post-Translational Protein Processing Proteins Proteome Pyruvate Regulation Reperfusion Injury Reporting Research Resolution Role SLC25A4 gene Signal Transduction Signaling Molecule Stress Testing Treatment Failure Work 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 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（GRK2）是GPCR回收和脱敏的关键调节剂这在几种心脏病理中被上调，包括肥大和心力衰竭（HF）。心脏缺血 - 再灌注损伤在S670诱导ERK介导的GRK2磷酸化，这导致 GRK2从细胞质转向线粒体的易位。我们发现在成人心肌细胞中线粒体GRK2通过抑制丙酮酸来调节葡萄糖介导的氧化磷酸化脱氢酶，葡萄糖氧化酶的速率限制酶。虽然线粒体的生理影响据报道GRK2，线粒体GRK2如何调节心脏线粒体仍然未知代谢。该提案的重点是从机械上解密GRK2磷酸化和线粒体易位调节心脏葡萄糖代谢。此外，我们提出了线粒体 GRK2通过充当的放大器来参与心肌梗死后的代谢信号传导（MI）凋亡 - 一种新型的裂解细胞死亡机制。因此，我们假设S670处的GRK2磷酸化为由于改变了代谢可用性和心脏损伤而导致心肌细胞反应的重要性。使用新型的GRK-S670A和两个Gasdermin E小鼠模型，我们建议执行两个具体目标：1。）确定mitogrk2如何调节心脏线粒体代谢； 2.）评估是否磷酸化是否 S670的GRK2调节心脏凋亡信号传导。总体而言，我们的工作将阐明GRK2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伤害反应。这项研究的总体目标是利用新颖的机械用于开发和鉴定新药用于HF治疗的信号传导。