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.

项目概要 G 蛋白偶联受体 (GPCR) 激酶 2 (GRK2) 是 GPCR 回收和脱敏的关键调节因子它在多种心脏病学中上调，包括肥厚和心力衰竭（HF）。心脏缺血再灌注损伤诱导 ERK 介导的 GRK2 S670 磷酸化，从而导致 GRK2 从细胞质易位至线粒体。我们发现在成人心肌细胞中线粒体GRK2通过抑制丙酮酸调节葡萄糖介导的氧化磷酸化脱氢酶，葡萄糖氧化的限速酶。尽管线粒体的生理影响 GRK2 被报道，但线粒体 GRK2 如何调节心脏线粒体仍知之甚少代谢。该提案的重点是从机制上破译 GRK2 磷酸化和线粒体易位调节心脏葡萄糖代谢。此外，我们建议线粒体 GRK2 通过充当心肌梗塞后 (MI) 的放大器来参与关键的代谢信号传导焦亡——一种新的裂解细胞死亡机制。因此，我们假设 GRK2 在 S670 处的磷酸化是由于改变代谢可用性和心脏损伤，对于心肌细胞反应至关重要。使用新型 GRK-S670A 和两个 Gasdermin E 小鼠模型，我们建议实现两个具体目标：1.) 确定 mitoGRK2 如何调节心脏线粒体代谢； 2.) 评估是否磷酸化 S670 处的 GRK2 调节心脏焦亡信号传导。总的来说，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损伤反应。这项研究的总体目标是开发新的机制开发和鉴定用于心力衰竭治疗的新药物的信号传导。