Metabolic Regulation of Mucosal Inflammation

粘膜炎症的代谢调节

• 批准号: 10427139
• 负责人: Sean P Colgan
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427139
• 关键词: Abscess; Acute; American; Antigens; Area; Brain; Cell Hypoxia; Cells; Cellular Metabolic Process; Chronic; Colitis; Creatine; Creatine Kinase; Crohn' s disease; Defect; Digestive System Disorders; Disease; Energy Metabolism; Environment; Epithelial; Epithelial Cells; Equilibrium; Etiology; Event; Flare; Gastrointestinal tract structure; Gene Expression; Gene Expression Regulation; Generations; Goals; High Pressure Liquid Chromatography; Homeostasis; Hospitalization; Hypoxia; Hypoxia Inducible Factor; Immune response; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Investigation; Investigational Therapies; Knockout Mice; Lead; Life; Mass Spectrum Analysis; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Mitochondria; Molds; Molecular; Mucositis; Mucous Membrane; Mus; Oxygen; Population; Protein Isoforms; Proteins; Regulation; Resolution; Ribonucleotides; Role; Shapes; Supplementation; Testing; Tight Junctions; Time; Tissues; Ulcerative Colitis; Validation; Western World; Work; adenylate; adenylate kinase; base; chemically induced colitis; chromatin immunoprecipitation; combinatorial; creatine transporter; defined contribution; design; dietary; energy balance; experimental study; gut inflammation; healing; hospitalization rates; human model; in vivo; insight; interest; intestinal barrier; intestinal crypt; intestinal epithelium; metabolomics; military patient; military service; military veteran; mouse model; novel; novel therapeutics; promoter; response; service member; stressor; transcription factor; wound healing

The Inflammatory Bowel Diseases (IBD), including Crohn's disease and ulcerative colitis, remain among the most debilitating inflammatory disorders of the western world. It is estimated that more than 1.5 million Americans suffer with IBD, with incidence rates on the rise in many populations. A recent study of more than 100,000 military service members estimated the incidence of IBD to be 2-10 times greater than non-service members, with a striking relationship between IBD incidence and the number of life stressors. The precise etiology of IBD is not known. Our interest is focused on the identification of inflammation-associated changes in tissue metabolsim during flares of IBD. These studies are founded on the observation that active intestinal inflammation in IBD is characterized by significant shifts in tissue metabolism that can influence cell and tissue function in fundamental ways. Under such conditions, epithelial cells have the capacity to dynamically control mucosal resolution and do so with a high degree of fidelity. The precise mechanisms by which metabolic pathways control resolution, however, have yet to be elucidated. Our work in progress has revealed that localized oxygen depletion (hypoxia) during inflammation significantly influences the metabolic demands of the tissue. In ongoing work, we have utilized global chromatin immunoprecipitation promoter arrays (ChIP-chip) in conjunction with detailed metabolomics to identify tractable metabolite targets in intestinal epithelial cells that control energy balance and barrier function. These studies have identified creatine and adenylate energy intermediates as checkpoint metabolites in epithelial barrier regulation during inflammation. In this proposal, we will define how epithelial metabolism molds the mucosal tissue environment during inflammation. Three synergistic specific aims are directed at testing the hypothesis that inflammation-associated changes within the tissue environment establishes metabolic control of inflammatory resolution through the promotion of mucosal barrier function. In Aim 1 will focus on defining the role of adenylate energy metabolism and AMP kinase activation in barrier regulation within the mucosa. Aim 2 will elucidate the function of creatine transport in the regulation of epithelial barrier function. Specific Aim 3 will elucidate the role of creatine transport and adenylate energy metabolism in barrier regulation and wound healing in vivo. It is our hope that these results will reveal new insights into innate regulation of mucosal inflammatory resolution and that extensions of this work will lead to targets for experimental therapeutics.

炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎， 仍然是西方世界最令人衰弱的炎症性疾病之一。据估计 超过150万美国人患有IBD，许多国家的发病率在上升， 人口。最近一项针对10万多名军人的研究估计， IBD的发病率是非服务人员的2-10倍， IBD发病率和生活压力源数量之间的关系。IBD的确切病因尚不清楚。 我们的兴趣集中在组织中炎症相关变化的识别上 IBD发作期间的代谢。这些研究是建立在这样的观察基础上的： IBD中的肠道炎症的特征在于组织代谢的显著变化， 从根本上影响细胞和组织功能。在这种情况下，上皮细胞 具有动态控制粘膜消退的能力， 忠诚然而，代谢途径控制分辨率的精确机制， 尚未阐明。我们正在进行的工作表明，局部缺氧（缺氧） 在炎症过程中，显著影响组织的代谢需求。在正在进行的工作中， 我们利用了全局染色质免疫沉淀启动子阵列（ChIP芯片） 通过详细的代谢组学来确定肠上皮细胞中易处理的代谢物靶点， 控制能量平衡和屏障功能。这些研究已经确定肌酸和腺苷酸 能量中间体作为检查点代谢物在上皮屏障调节中的作用 炎症 在这个建议中，我们将定义上皮代谢如何塑造粘膜组织 炎症时的环境。三个协同的具体目标是针对测试 假设组织环境内的炎症相关变化建立了 通过促进粘膜屏障功能来代谢控制炎症消退。在 目的1将集中于确定腺苷酸能量代谢和AMP激酶激活在 粘膜内的屏障调节。目的2将阐明肌酸转运在心肌细胞中的作用。 调节上皮屏障功能。具体目标3将阐明肌酸转运的作用 以及腺苷酸能量代谢在体内屏障调节和伤口愈合中的作用。我们希望 这些结果将揭示对粘膜炎症消退的先天调节的新见解 这项工作的延伸将导致实验性治疗的目标。