Molecular Pharmacology of Insulin Resistance in Burns

烧伤胰岛素抵抗的分子药理学

基本信息

批准号：
7585601
负责人：
Jeevendra Martyn
金额：
$ 39.07万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7585601
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Adenoviruses Anabolism Animals Anti-Inflammatory Agents Anti-inflammatory Area Area Under Curve Attenuated Binding Proteins Biotin Boxing Burn injury Butyric Acid Butyric Acids Carbohydrates Carbon Dioxide Catabolism Cells Conflict (Psychology)Critical Illness Cultured Cells Cyclic GMP Cysteine Data Depressed mood Diabetes Mellitus Diabetic mouse Disruption Dithiothreitol Dose Embryo Endoplasmic Reticulum Endotoxemia Endotoxins Eukaryotic Initiation Factors Exposure to Fatty Liver Fatty acid glycerol esters Fibroblasts Figs - dietary Functional disorder Genes Gluconeogenesis Glucose tolerance test Glycogen Glycogen (Starch) Synthase Glycogen Synthase Kinase 3 Glycogen Synthase Kinases HYOU1 gene Hepatic Hormones Hyperglycemia Immobilization In Vitro Inflammation Inflammation Mediators Inflammatory Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway Interferons Interleukins Knock-out Knockout Mice LacZ Genes Leptin Lipopolysaccharides Liver Mass Spectrum Analysis Mediating Mediation Mediator of activation protein Metabolic Methods Molecular Molecular Chaperones Morbidity - disease rate Mus Muscle Muscle Cells Muscle Fibers Muscle Proteins N-acetylpenicillamine Neurons Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Oxidation-Reduction Oxidoreductase Pancreas Pathogenesis Pathologic Pharmacology Pharmacotherapy Phosphate Buffer Phosphoenolpyruvate Carboxylase Phosphotransferases Play Post-Translational Protein Processing Production Protein Biosynthesis Protein Overexpression Protein Synthesis Inhibition Proteins Proteomics Proto-Oncogene Proteins c-akt Public Health RNA Reaction Reactive Nitrogen Species Reduced Glutathione Reporting Research Resistance Respiratory Failure Reticulum Right-On Rodent Role S-nitro-N-acetylpenicillamine SKIL gene Saline Signal Pathway Signal Transduction Signaling Protein Skeletal Muscle Skeletal system Small Interfering RNA Solid Stress Substrate Cycling Sulfhydryl Compounds Taurine Testing Text Therapeutic Intervention Thinking Tissues Transgenic Mice Transgenic Organisms Trauma Tumor Necrosis Factor-alpha Tumor Necrosis Factors Ubiquitin Upstream Enhancer Ursodeoxycholic Acid Wild Type Mouse Work aminoguanidine attenuation base biological adaptation to stress cell type cytokine diabetic eIF-2 Kinase glucose uptake glucose-regulated proteins glycemic control human NOS2A protein human NOS3 protein human TNF protein human TYRP1 protein human disease improved in vivo inhibitor/antagonist insulin receptor substrate 1 protein insulin sensitivity insulin signaling insulin tolerance macrophage mortality mouse S-nitrosoglutathione reductase novel therapeutics oxygen-regulated proteins pre-clinical prevent protective effect prototype response stress-activated protein kinase 1 tauroursodeoxycholic acid transcription factor transcription factor CHOP wasting

1-Phosphatidylinositol 3-Kinase Abbreviations Adenoviruses Anabolism Animals Anti-Inflammatory Agents Anti-inflammatory Area Area Under Curve Attenuated Binding Proteins Biotin Boxing Burn injury Butyric Acid Butyric Acids Carbohydrates Carbon Dioxide Catabolism Cells Conflict (Psychology)Critical Illness Cultured Cells Cyclic GMP Cysteine Data Depressed mood Diabetes Mellitus Diabetic mouse Disruption Dithiothreitol Dose Embryo Endoplasmic Reticulum Endotoxemia Endotoxins Eukaryotic Initiation Factors Exposure to Fatty Liver Fatty acid glycerol esters Fibroblasts Figs - dietary Functional disorder Genes Gluconeogenesis Glucose tolerance test Glycogen Glycogen (Starch) Synthase Glycogen Synthase Kinase 3 Glycogen Synthase Kinases HYOU1 gene Hepatic Hormones Hyperglycemia Immobilization In Vitro Inflammation Inflammation Mediators Inflammatory Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway Interferons Interleukins Knock-out Knockout Mice LacZ Genes Leptin Lipopolysaccharides Liver Mass Spectrum Analysis Mediating Mediation Mediator of activation protein Metabolic Methods Molecular Molecular Chaperones Morbidity - disease rate Mus Muscle Muscle Cells Muscle Fibers Muscle Proteins N-acetylpenicillamine Neurons Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Oxidation-Reduction Oxidoreductase Pancreas Pathogenesis Pathologic Pharmacology Pharmacotherapy Phosphate Buffer Phosphoenolpyruvate Carboxylase Phosphotransferases Play Post-Translational Protein Processing Production Protein Biosynthesis Protein Overexpression Protein Synthesis Inhibition Proteins Proteomics Proto-Oncogene Proteins c-akt Public Health RNA Reaction Reactive Nitrogen Species Reduced Glutathione Reporting Research Resistance Respiratory Failure Reticulum Right-On Rodent Role S-nitro-N-acetylpenicillamine SKIL gene Saline Signal Pathway Signal Transduction Signaling Protein Skeletal Muscle Skeletal system Small Interfering RNA Solid Stress Substrate Cycling Sulfhydryl Compounds Taurine Testing Text Therapeutic Intervention Thinking Tissues Transgenic Mice Transgenic Organisms Trauma Tumor Necrosis Factor-alpha Tumor Necrosis Factors Ubiquitin Upstream Enhancer Ursodeoxycholic Acid Wild Type Mouse Work aminoguanidine attenuation base biological adaptation to stress cell type cytokine diabetic eIF-2 Kinase glucose uptake glucose-regulated proteins glycemic control human NOS2A protein human NOS3 protein human TNF protein human TYRP1 protein human disease improved in vivo inhibitor/antagonist insulin receptor substrate 1 protein insulin sensitivity insulin signaling insulin tolerance macrophage mortality mouse S-nitrosoglutathione reductase novel therapeutics oxygen-regulated proteins pre-clinical prevent protective effect prototype response stress-activated protein kinase 1 tauroursodeoxycholic acid transcription factor transcription factor CHOP wasting

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项目摘要

DESCRIPTION (provided by applicant): Insulin resistance is the major metabolic abnormality associated with burn injury. All insulin-mediated effects, including glucose uptake in tissues, protein synthesis, inhibition of gluconeogenesis and anti-inflammatory functions, are markedly attenuated. Supraphysiologic doses of exogenous insulin to counter burn-induced insulin resistance produce deleterious effects, including increased CO2 production and hepatic steatosis. Burn injury alters the insulin signaling pathway at multiple points, via the insulin receptor, insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3-K), Akt/PKB (protein kinase B), and glycogen synthase kinase-32 (GSK-32). Although inducible nitric oxide synthase (iNOS) is thought to play an important role in the deranged insulin-signaling, the molecular mechanisms by which iNOS mediates these changes are unknown. Specific Aim 1 will test the hypothesis that the de-nitrosylation reaction, regulated by S-nitrosoglutathione reductase (GSNOR), plays an important protective role in burn-induced insulin resistance in mice. It is hypothesized that nitrosative stress by iNOS leads to increased protein S-nitrosylation (post-translational modification) of the insulin-signaling proteins resulting in depressed insulin signaling. To test this hypothesis, insulin sensitivity, glucose uptake in muscle, insulin signaling, and S-nitrosylation (by proteomics) of the insulin-signaling proteins will be evaluated in muscle from sham-burned or burned wild-type, GSNOR knockout (-/-) and GSNOR/ iNOS- /- double knockout mice. The protective role of GSK-32 inhibitors in obesity-induced insulin resistance is established, but the molecular mechanism of GSK-32 activation and the salutary effects of GSK-32 inhibitors remain to be investigated particularly in skeletal muscle. Specific Aim 2 will test the hypothesis that (1) iNOS- mediated increased activity of GSK-32 plays an important role in burn-induced insulin resistance; (2) S- nitrosylation is involved in iNOS-mediated GSK-32 activation after burn injury; and (3) GSK-32 activation reduces IRS-1 expression as a downstream effector of iNOS in skeletal muscle. Specific Aim 3 will test the hypothesis that endoplasmic reticulum (ER) stress response plays an important role in muscle insulin resistance of burns, and that iNOS functions both as a downstream effector and an upstream enhancer of ER stress in skeletal muscle. The planned studies will use: XBP-1 , skeletal muscle-specific ORP150 over- expressing transgenic, GSNOR-/-, iNOS-/- and GSNOR/iNOS-/- double knockout mice to test these hypotheses. (XBP-1 is a transcription factor regulating ER chaperones and ORP150 protects cells from ER stress.) Thus, these studies will apply an integrated molecular, pharmacologic, and proteomic approach to elucidate the molecular mechanism by which iNOS, GSNOR, GSK-32, and ER stress interrelate to produce insulin resistance, and will provide a rationale and preclinical data for novel therapeutic interventions to treat insulin resistance in muscle after burns. PUBLIC HEALTH RELEVANCE: The proposed studies will apply integrated molecular, pharmacologic, and proteomic approaches to elucidate the molecular mechanism by which inducible nitric oxide and endoplasmic stress reticulum interact with each other and insulin signaling proteins to cause insulin resistance in burns

描述（由申请人提供）：胰岛素抵抗是与烧伤损伤相关的主要代谢异常。所有胰岛素介导的作用，包括组织中的葡萄糖摄取，蛋白质合成，糖异生的抑制和抗炎功能，都显着减弱。外源性胰岛素的超生理剂量以抗燃烧诱导的胰岛素抵抗会产生有害作用，包括增加的二氧化碳产生和肝脂肪变性。通过胰岛素受体，胰岛素受体底物-1（IRS-1），磷脂酰肌醇3-激酶（PI3-K），AKT/PKB（蛋白激酶B）和Glycogen合成激酶激酶-32（GSK-32（GSK-32））。尽管诱导型一氧化氮合酶（iNOS）被认为在混乱的胰岛素信号中起重要作用，但iNOS介导这些变化的分子机制尚不清楚。具体的目标1将检验以下假设：由S-硝基谷硫硫代还原酶（GSNOR）调控的亚硝基化反应在小鼠中燃烧诱导的胰岛素抵抗中起重要的保护作用。假设iNOS的亚硝化应激导致胰岛素 - 信号蛋白的蛋白S-硝基化（翻译后修饰）增加，从而导致胰岛素信号降低。 To test this hypothesis, insulin sensitivity, glucose uptake in muscle, insulin signaling, and S-nitrosylation (by proteomics) of the insulin-signaling proteins will be evaluated in muscle from sham-burned or burned wild-type, GSNOR knockout (-/-) and GSNOR/ iNOS- /- double knockout mice. GSK-32抑制剂在肥胖诱导的胰岛素抵抗中的保护作用已建立，但是GSK-32激活的分子机制和GSK-32抑制剂的有益作用仍有待研究，尤其在骨骼肌中待研究。特定的目标2将检验以下假设：（1）iNOS介导的GSK-32活性在燃烧诱导的胰岛素抵抗中起重要作用。（2）S-硝基化参与烧伤后iNOS介导的GSK-32激活；（3）GSK-32激活将IRS-1表达降低为骨骼肌中iNOS的下游效应子。具体目标3将检验以下假设：内质网应力反应在烧伤的肌肉胰岛素抵抗中起重要作用，并且iNOS既是下游效应器又是骨骼肌中ER应激的上游增强子。计划研究将使用：XBP-1，骨骼肌特异性ORP150过度表达转基因，GSNOR - / - ，INOS - / - 和GSNOR/INOS - / - 双敲除小鼠，以检验这些假设。（XBP-1是调节ER伴侣伴侣的转录因子，ORP150可保护细胞免受ER压力。）因此，这些研究将应用分子，药理和蛋白质组学方法的综合方法来阐明分子机制，INOS，GSNOR，GSNOR，GSNOR，GSNOR，GSK-32，并为胰岛压力提供了用于胰岛素的胰岛素和预处理，并将其用于胰岛素，并将其用于胰岛素的抵抗力，并将其用于胰岛素的电阻，并将其用于胰岛素，并将其用于胰岛素，并将其用于胰岛素的电阻，并将其用于胰岛素。燃烧后肌肉中的胰岛素抵抗。公共卫生相关性：拟议的研究将采用综合分子，药理和蛋白质组学方法来阐明诱导型一氧化氮和内质应激网状网状彼此相互作用的分子机制，并相互相互作用，并引起胰岛素信号蛋白在燃烧中引起胰岛素抵抗