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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.

项目概要/摘要糖尿病心肌病是一种复杂的疾病，是由于长期过量使用脂肪酸导致的由于缺乏胰岛素信号和葡萄糖摄取而促进糖尿病心肌的收缩功能利用率。糖尿病心肌几乎完全使用脂肪酸作为燃料，导致广泛的代谢组学变化失调导致膜结构和功能发生多种有害改变。期间目前的资助间隔，我们已经利用我们开发的质谱技术来确定糖尿病心肌中存在大量新型信号分子，我们假设这些分子对糖尿病心肌的生物能低效率和适应不良信号传导。我们建议这些新颖的信号分子导致患有急性冠脉综合征的糖尿病患者死亡率增加心肌梗塞（MI）。此外，这些信号通路病理改变的后果糖尿病心肌导致糖尿病患者 MI 后 5 年预后不良，包括生物能导致血流动力学损害并促进线粒体功能障碍的改变糖尿病心肌病。脂质在细胞功能中发挥多效性作用，包括能量产生的底物心肌。糖尿病心肌病的一个主要方面是脂质的适应不良和功能失调。代谢和利用从而导致有毒信号分子的产生。此前，通过通过遗传、药理学和化学生物学方法，我们已经确定了三种主要的磷脂酶和心肌中的脂肪酶 iPLA2ß (PNPLA9)、iPLA2γ (PNPLA8) 和 iPLA2ζ (PNPLA2; ATGL) 可能充当心肌血流动力学功能障碍、电生理改变和适应不良的主要介质糖尿病心肌重塑。最近，我们证明了 iPLA2γ 及其下游信号传导代谢物启动转化信号通路，这可能是许多多种有害物质的基础糖尿病心肌的变化明显。因此，在具体目标 1 中，我们将使用我们的质量支持套件光谱技术来鉴定由此产生的新型信号分子的类型和数量途径并通过系统生物学方法确定其功能，以确定其在启动过程中的具体作用和糖尿病心肌病的传播。在具体目标 2 中，我们发现了一种新的激活机制 iPLA2ß。因此，我们将确定激活的 iPLA2ß 在介导适应不良产生中的作用糖尿病心肌中的信号代谢物和导致缺血的糖尿病心肌中的信号代谢物。在具体目标 3 中，我们将追踪糖尿病心肌中甘油三酯分子种类的巨大变化，该变化在水解后 iPLA2ζ（PNPLA2；ATGL）可能会促进糖尿病心肌中信号传导功能障碍。总的来说，这些研究是一种协同的多学科方法，用于确定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遗传功能丧失小鼠来提供药物发现和突出药理靶点转化为临床的快速通道方法。