REGULATION OF MYOCARDIAL PHOSPHOLIPASES AND LIPASES IN DIABETIC MYOCARDIUM

糖尿病心肌中心肌磷脂酶和脂肪酶的调节

基本信息

批准号：
9309220
负责人：
RICHARD W GROSS
金额：
$ 76.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309220
关键词：
Affinity Affinity Chromatography Animal Model Arachidonic Acids Arrhythmia Attenuated Binding Proteins Bioenergetics Biological Biology Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Calmodulin Calpain Cardiac Cardiac Myocytes Cell physiology Cells Characteristics Chemicals Chronic Cleaved cell Clinic Complex Cyclic AMP Development Diabetes Mellitus Diglycerides Disease Dissection Eicosanoids Electrophysiology (science)Enzymes Epidemic Exercise Family Fatty Acids Fatty acid glycerol esters Functional disorder Genetic Glucose Grant Heart Heart Diseases Heart Hypertrophy Hydrolysis Industrialization Infarction Inflammation Inflammation Mediators Insulin Resistance Knockout Mice Lead Lipase Lipids Lipoxygenase Mediating Mediator of activation protein Membrane Structure and Function Metabolism Molecular Monoglycerides Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Natural Products Oxidases Oxides Oxygen Consumption PLA2G6 gene Pathologic Pathway interactions Performance Pharmaceutical Preparations Pharmacology Phospholipase Phospholipids Phosphorylation Production Prostaglandin-Endoperoxide Synthase Protein Isoforms Protein Kinase C Proteins Proteolysis Proteomics Protons Regulation Research Role Seminal Signal Pathway Signal Transduction Signaling Molecule Societies Source Specificity Stable Isotope Labeling Surface Plasmon Resonance Systems Biology Technology Transacylase Transferase Transgenic Organisms Translations Triglycerides acute coronary syndrome analog arm design diabetic diabetic cardiomyopathy diabetic patient drug discovery enantiomer experimental study frontier gain of function glucose uptake hemodynamics in vivo insulin signaling interdisciplinary approach lipid metabolism loss of function magnetic beads metabolomics mitochondrial dysfunction monoolein mortality novel outcome forecast oxidation receptor transacylation transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Diabetic cardiomyopathy is a complex disorder that emanates from the chronic and excessive use of fatty acids to fuel contractile function in diabetic myocardium due to the lack of insulin signaling and glucose uptake and utilization. The nearly exclusive use of fatty acids for fuel in diabetic myocardium results in widespread metabolomic dysregulation that precipitates multiple deleterious alterations in membrane structure and function. During the current grant interval, we have utilized enabling mass spectrometric technologies we developed to identify a plethora of novel signaling molecules in diabetic myocardium which we hypothesize contribute significantly to the bioenergetic inefficiency and maladaptive signaling in diabetic myocardium. We propose that these novel signaling molecules contribute to the increased mortality of diabetic patients suffering from acute coronary syndromes leading to myocardial infarction (MI). Moreover, the consequences of these pathologic alterations in signaling pathways in diabetic myocardium lead to the poor 5 year prognosis of diabetic patients after MI and include bioenergetic alterations that precipitate hemodynamic compromise, and promote mitochondrial dysfunction characteristic of diabetic cardiomyopathy. Lipids serve pleiotropic roles in cell function including substrate for energy production in myocardium. A primary aspect of diabetic cardiomyopathy is the maladaptive and dysfunctional integration of lipid metabolism with utilization thereby resulting in the production of toxic signaling molecules. Previously, through genetic, pharmacologic and chemical biological approaches, we have identified three major phospholipases and lipases in myocardium iPLA2ß (PNPLA9), iPLA2γ (PNPLA8), and iPLA2ζ (PNPLA2; ATGL) that likely serve as principal mediators of myocardial hemodynamic dysfunction, electrophysiologic alterations and maladaptive remodeling in diabetic myocardium. Recently, we demonstrated that iPLA2γ and its downstream signaling metabolites initiate a transformative signaling pathway which likely underlies many of the multiple deleterious changes manifest in diabetic myocardium. Accordingly, in Specific Aim 1, we will use our enabling suites of mass spectrometric technologies to identify the types and amounts of novel signaling molecules produced by this pathway and identify their functions through a systems biology approach to define their specific roles in the initiation and propagation of diabetic cardiomyopathy. In Specific Aim 2, we have identified a novel mechanism activating iPLA2ß. Accordingly, we will identify the role of activated iPLA2ß in mediating the maladaptive production of signaling metabolites in diabetic myocardium and in diabetic myocardium rendered ischemic. In Specific Aim 3, we will pursue the dramatic changes in triglyceride molecular species in diabetic myocardium which, after hydrolysis by iPLA2ζ (PNPLA2; ATGL), likely promote dysfunctional signaling in diabetic myocardium. Collectively, these studies are a synergistic multidisciplinary approach to identify the chemical mechanisms mediating diabetic cardiomyopathy using three highly relevant animal models of diabetes in conjunction with genetic loss of function mice to provide a fast track approach to drug discovery and translation of prominent pharmacologic targets to the clinic.

项目摘要/摘要糖尿病心肌病是一种复杂的疾病，它从慢性和过量使用脂肪酸到由于缺乏胰岛素信号传导和葡萄糖摄取和糖尿病心肌的燃料转化器功能利用率。糖尿病心肌中脂肪酸几乎独有的用法可导致宽度代谢组学膜结构和功能中多个删除的变化的失调失调。在当前的赠款间隔，我们利用了启用质谱技术，我们开发了糖尿病心肌中的大量新型信号分子，我们假设这对糖尿病心肌中的生物能无效和适应不良的信号传导。我们提出这些新颖的信号分子导致患有急性冠状动脉综合征的糖尿病患者的死亡率增加到心肌梗塞（MI）。此外，这些病理变化在信号通路中的后果糖尿病心肌导致MI后糖尿病患者的5年预后不良，并包括生物能导致血液动力学妥协并促进线粒体功能障碍的变化特征糖尿病心肌病。脂质在细胞功能中发挥了多效性作用，包括用于产生能量的底物心肌。糖尿病心肌病的主要方面是脂质的适应不良和功能失调的整合新陈代谢具有利用，从而导致有毒信号分子的产生。以前，通过遗传，药物和化学生物学方法，我们已经确定了三个主要的磷脂酶， IPLA2ß（PNPLA9），IPLA2γ（PNPLA8）和IPLA2ζ（PNPLA2; ATGL）中的脂肪酶，可能用作心肌血液动力学功能障碍，电生理改变和适应不良的主要介质重塑糖尿病心肌。最近，我们证明了IPLA2γ及其下游信号代谢产物启动了一个变换信号通路，该途径可能是许多有害的基础变化体现在糖尿病心肌中。据特定目标1中的说法，我们将使用我们的质量套件光谱技术识别此产生的新型信号分子的类型和量途径并通过系统生物学方法来确定其功能，以定义其在主动性中的特定角色和糖尿病心肌病的传播。在特定目标2中，我们确定了一种新型机制激活 ipla2ß。彼此之间，我们将确定活化的IPLA2ß在介导适应不良的产生中的作用糖尿病心肌和糖尿病心肌中的信号代谢产物引起缺血。在特定的目标3中，我们将在糖尿病心肌中纯化甘油三酸酯分子物种的急剧变化，该物种在水解后通过 IPLA2ζ（PNPLA2； ATGL），可能促进糖尿病心肌中功能障碍信号传导。总的来说，这些研究是一种协同的多学科方法，用于识别介导糖尿病心肌病的化学机制使用三种高度相关的糖尿病动物模型以及功能小鼠的遗传丧失快速轨道方法发现药物发现和转化为诊所的著名药理靶标。