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NOVEL LIPID 2ND MESSENGERS REGULATING BIOENERGETICS AND SIGNALING IN HUMAN MYOCARDIUM

调节人体心肌生物能量和信号传导的新型脂质第二信使

基本信息

批准号：
9281066
负责人：
RICHARD W GROSS
金额：
$ 38.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9281066
关键词：
Aldehydes Animal Model Apoptosis Apoptotic Arachidonic Acids Attenuated Biochemical Pathway Bioenergetics Calcium Cardiac Cardiac Myocytes Cardiolipins Cell Death Cells Cellular biology Charge Chemicals Chemistry Column Chromatography Consumption Coupled Coupling Cyclic AMP Dinoprostone Eicosanoids Enzymes Ethers Fatty acid glycerol esters Fibroblasts Functional disorder Generations Goals Heart Heart Diseases Heart Mitochondria Heart Transplantation Heart failure High Pressure Liquid Chromatography Human Hydrolysis Hydroxyeicosatetraenoic Acids Hydroxyl Radical Incubated Individual Inflammation Ions Lipid Biochemistry Lipids Lysophosphatidylcholines Lysophospholipids Mediating Mediator of activation protein Membrane Membrane Potentials Metabolic Metabolism Mitochondria Molecular Mus Myocardial Myocardium Natural Products Nature Organelles Oxides PTGS2 gene Pathway interactions Permeability Pharmacology Phosphatidylinositol 4,5-Diphosphate Phospholipids Physiology Plasmalogens Process Production Prostaglandin-Endoperoxide Synthase Reaction Research Resolution Respiratory physiology Role Series Signal Transduction Signaling Molecule Stable Isotope Labeling Stress Technology arachidonate cell type cyclooxygenase 1 cyclooxygenase 2 cytochrome c cytokine drug discovery fatty aldehyde gain of function genetic manipulation insight isotope incorporation lipid mediator lipid metabolism loss of function macrophage mitochondrial dysfunction mouse model multiple reaction monitoring new technology novel novel strategies oxidation oxidized lipid plasmenylcholine receptor-mediated signaling respiratory response stereochemistry sugar translational approach vinyl ether

项目摘要

ABSTRACT Mitochondria are essential subcellular organelles that serve multiple functions in cellular biology including energy production, metabolism, lipid synthesis and signaling. Due to the ease of genetic manipulation in mouse models, a large majority of mechanistic inferences about heart failure have been made from gain of function or loss of function studies of specific enzymes during heart failure in mice. However, profound differences in the chemistry and physiology of murine mitochondria are present in comparison to human mitochondria. These include vast differences between murine and human mitochondrial phospholipid compositions, their repertoires of lipid 2nd messengers generated in response to stress, and the enzymic mediators responsible for modulating human mitochondrial signaling and bioenergetics. To bridge the translational gap between mouse and humans, we have focused our studies on the roles of lipid 2nd messengers present in human hearts and their impact on human heart mitochondrial bioenergetic and signaling functions. Recently, we have discovered a series of novel lipid 2nd messengers generated by human mitochondria which are dynamically regulated during the progression of heart failure in humans. Moreover, we have demonstrated that these novel lipid 2nd messengers modulate human mitochondrial energy production, bioenergetic efficiency and cellular signaling. Accordingly, a major goal of the proposed research is to identify the chemical mechanisms that integrate mitochondrial function with human cardiac myocyte physiology through novel lipid 2nd messengers we identified in human myocardium. Through utilization of an integrated series of mass spectrometric technologies we developed/employ including LC-MS/MS with charge-switch derivatization, multiple reaction monitoring, and high mass accuracy analysis of suites of product ions, we have identified and quantified many new natural products some of which we have already been shown to modulate human mitochondrial bioenergetics and signaling. The first goal is to identify the molecular mechanisms which initiate the generation of these novel lipid 2nd messengers from human myocardial phospholipids and identify the biochemical pathways which generate these natural products. The second goal of the proposed research is to identify the chemical diversity of these natural products and clarify their enantiomeric purity in extracts of human myocardium. Identification of enantiomerically pure natural products in human myocardium will demonstrate that they are produced by specific enzymes and that they are not products of adventitious oxidation. The third goal of the proposed studies is to mechanistically identify their roles in modulating human heart mitochondrial bioenergetics and signaling. Collectively, the proposed research is a unique opportunity to dramatically accelerate identification of the roles of human heart lipid 2nd messengers in precipitating human mitochondrial dysfunction that promotes the progression of human heart failure. This targeted translational approach will directly identify bona fide pharmacologic targets for treatment of human heart failure.

摘要