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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.

摘要线粒体是重要的亚细胞器，在细胞生物学中发挥多种功能，包括能量产生、代谢、脂质合成和信号传导。由于基因操作的容易性，在小鼠模型中，大多数关于心力衰竭的机械推断是从获得小鼠心力衰竭期间特定酶的功能或功能丧失研究。然而，深刻的与人类相比，存在小鼠线粒体的化学和生理学差异线粒体这些包括鼠和人的线粒体磷脂之间的巨大差异组成，他们的剧目的脂质第二信使产生的压力，和酶，负责调节人类线粒体信号传导和生物能量学的介质。弥合由于小鼠和人类之间的翻译差距，我们将研究重点放在脂质2nd的作用上，人类心脏中存在的信使及其对人类心脏线粒体生物能和信号功能。近年来，我们发现了一系列新的脂质第二信使，线粒体，其在人类心力衰竭的进展期间被动态调节。而且我们已经证明这些新的脂质第二信使调节人线粒体能量产生，生物能量效率和细胞信号传导。因此，拟议研究的一个主要目标是确定整合线粒体功能与人类心肌细胞生理学的化学机制通过我们在人类心肌中发现的新型脂质第二信使。通过利用综合我们开发/采用的一系列质谱技术，包括LC-MS/MS电荷开关衍生化、多反应监测和高质量准确度分析的产品离子套件，我们有鉴定和量化了许多新的天然产物，其中一些我们已经被证明可以调节人类线粒体生物能量学和信号传导。第一个目标是确定分子机制，启动从人心肌磷脂产生这些新的脂质第二信使，并鉴定产生这些天然产物的生化途径。拟议研究的第二个目标是确定这些天然产物的化学多样性，并澄清其对映体纯度的提取物，人体心肌人心肌组织中对映体纯天然产物的鉴定证明它们是由特定的酶产生的，它们不是外源性的产物。氧化所提出的研究的第三个目标是从机制上确定它们在调节人类免疫功能中的作用。心脏线粒体生物能量学和信号传导。总的来说，拟议的研究是一个独特的机会，大大加快了人类心脏脂质第二信使在人类心脏疾病中的作用的鉴定，线粒体功能障碍，促进人类心力衰竭的进展。这种靶向翻译该方法将直接识别用于治疗人类心力衰竭的真正药理学靶点。