Metabolic Regulation of Mucosal Inflammation

粘膜炎症的代谢调节

• 批准号: 8632796
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632796
• 关键词: Abscess; Acute; American; Automobile Driving; Binding; Cells; ChIP-on-chip; Chronic; Colitis; Colon Carcinoma; Creatine; Creatine Kinase; Crohn' s disease; Dendritic Cells; Diet; Disease; Disease Outcome; Disease model; Epithelial; Epithelial Cells; Etiology; Event; Gastrointestinal tract structure; Gene Targeting; Generations; Genes; Goals; Healed; Hospitalization; Human; Hypoxia; Hypoxia Inducible Factor; Immune response; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Lead; Lesion; Leukocytes; Malignant Neoplasms; Maps; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Military Personnel; Modeling; Molds; Molecular; Monitor; Mucositis; Mus; Myelogenous; Oxygen; Patients; Phenotype; Population; Protein Isoforms; Regulation; Research Design; Resolution; Role; Shapes; Testing; Therapeutic; Tissues; Translating; Ulcerative Colitis; Veterans; Western World; Work; bHLH-PAS factor HLF; base; chromatin immunoprecipitation; effective therapy; healing; hypoxia inducible factor 1; in vivo; insight; interest; intestinal crypt; macrophage; metabolomics; neutrophil; novel; novel therapeutics; promoter; public health relevance; research study; transcription factor

The Inflammatory Bowel Diseases (IBD), including Crohn's disease and ulcerative colitis, remain one of 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. Among military veterans, IBD has one of the highest hospitalization rates of all diseases. Moreover, IBD-related cancer incidence is on the rise in some veteran populations. The precise etiology of IBD is not known. Inflammatory responses associated with IBD are characterized by precise molecular interactions between epithelial cells and leukocytes, including neutrophils, macrophages, and dendritic cells. Our ongoing studies have revealed that migrating neutrophils establish microenvironmental control of metabolism within inflammatory lesions. Under such conditions, epithelial cells have the capacity to dynamically control mucosal resolution and do so with a high degree of fidelity. It is only recently appreciated that inflammation-associated changes in metabolism are central to the inflammatory response. Indeed, the interactions of metabolism with the transcriptional and translational machinery significantly influence disease outcomes. The precise mechanisms by which metabolic pathways control resolution, however, have yet to be established. 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 focused on defining how the transcription factor hypoxia-inducible factor (HIF) shapes the microenvironment of the inflammatory lesion. Using global chromatin immunoprecipitation promoter arrays (ChIP-chip) in conjunction with detailed NMR-based metabolomics, we have identified tractable HIF-specific targets in intestinal epithelial cells that control barrier function, particularly as they relate to rapid energy utilization (e.g. creatine kinase and the generation of phospho-creatine). In this proposal, we will define how epithelial metabolism molds the microenvironment during inflammation in the GI tract. Our project will place a particular emphasis on early events of the inflammatory response. Three synergistic specific aims are directed at testing the hypothesis that inflammation-associated changes within the microenvironment establishes metabolic control inflammatory resolution. In Aim 1, we will define the functional implications of creatine metabolism in acute colonic inflammation. Aim 2 will focus on the contribution of acute inflammatory cells to microenvironmental control of metabolic in vitro and in vivo. Specific Aim 3 will elucidate the role of epithelial HIF-1 and HIF-2 specific metabolites and extend these findings to understand how such changes translate in chronic inflammation. 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， 是西方世界最令人虚弱的炎症性疾病之一据估计，超过1.5 数百万美国人患有IBD，许多人群的发病率都在上升。是担任军事 IBD是所有疾病中住院率最高的疾病之一。此外，IBD相关的癌症 在一些退伍军人群体中发病率正在上升。IBD的确切病因尚不清楚。 与IBD相关的炎症反应以精确的分子相互作用为特征 上皮细胞和白细胞，包括中性粒细胞、巨噬细胞和树突状细胞之间。我们 正在进行的研究表明，迁移的中性粒细胞建立微环境控制， 炎症病变内的代谢。在这样的条件下，上皮细胞有能力 动态地控制粘膜分辨率，并以高度的保真度来实现。 最近才认识到，炎症相关的代谢变化是炎症的核心。 炎症反应。事实上，代谢与转录和翻译的相互作用 机械显著影响疾病结果。代谢途径的精确机制 然而，控制决议尚未确立。 正在进行的工作表明，炎症过程中的局部缺氧（缺氧） 显著影响组织的代谢需求。在正在进行的工作中，我们着重于定义 转录因子缺氧诱导因子（HIF）如何塑造炎症微环境 损伤。使用全局染色质免疫沉淀启动子阵列（ChIP芯片）结合详细的 基于NMR的代谢组学，我们已经确定了肠上皮细胞中易于处理的HIF特异性靶点， 控制屏障功能，特别是当它们涉及快速能量利用时（例如肌酸激酶和 产生磷酸肌酸）。 在这个建议中，我们将定义上皮代谢如何塑造微环境， 胃肠道炎症。我们的项目将特别强调炎症的早期事件， 反应三个协同的具体目标是针对测试的假设，炎症相关的 微环境内的变化建立了代谢控制炎症消退。在目标1中，我们 明确肌酸代谢在急性结肠炎症中的作用。目标2将侧重于 急性炎症细胞对体外和体内代谢微环境控制的贡献。具体 目的3将阐明上皮细胞HIF-1和HIF-2特异性代谢产物的作用，并将这些发现扩展到 了解这些变化如何转化为慢性炎症。 我们希望，这些结果将揭示新的见解先天调节粘膜 炎症消退和这项工作扩展将导致实验治疗的目标。