Metabolic Regulation of Mucosal Inflammation

粘膜炎症的代谢调节

• 批准号: 9339524
• 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/9339524
• 关键词: Abscess; Acute; American; Automobile Driving; Binding; Cells; Cellular Metabolic Process; Chronic; Colitis; Colon Carcinoma; Creatine; Creatine Kinase; Crohn' s disease; Dendritic Cells; Diet; Disease; Disease Outcome; Disease model; Epithelial; Epithelial Cells; Etiology; Event; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Targeting; Generations; Genes; Genetic Transcription; Goals; Hospitalization; Human; Hypoxia; Hypoxia Inducible Factor; Immune response; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Investigational Therapies; Lead; Lesion; Leukocytes; Malignant Neoplasms; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Military Personnel; Modeling; Molds; Molecular; Monitor; Mucositis; Mus; Myelogenous; Oxygen; Patients; Phenotype; Phosphocreatine; Population; Protein Isoforms; Recruitment Activity; Regulation; Resolution; Role; Shapes; Testing; Tissues; Translating; Ulcerative Colitis; Veterans; Western World; Work; bHLH-PAS factor HLF; base; chromatin immunoprecipitation; design; effective therapy; experimental study; healing; hypoxia inducible factor 1; in vivo; inflammatory milieu; insight; interest; intestinal crypt; macrophage; metabolic profile; metabolomics; neutrophil; novel; novel therapeutics; promoter; public health relevance; transcription factor

DESCRIPTION (provided by applicant): 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 t 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.

描述（由申请人提供）： 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，许多人群的发病率都在上升。在退伍军人中，IBD是所有疾病中住院率最高的疾病之一。此外，IBD相关癌症的发病率在一些退伍军人群体中呈上升趋势。IBD的确切病因尚不清楚。 与IBD相关的炎症反应的特征在于上皮细胞和白细胞（包括中性粒细胞、巨噬细胞和树突细胞）之间的精确分子相互作用。我们正在进行的研究表明，迁移的中性粒细胞在炎症病变内建立代谢的微环境控制。在这样的条件下，上皮细胞具有动态控制粘膜分辨率的能力，并且以高度的保真度这样做。 只是最近才认识到，炎症相关的代谢变化是炎症反应的核心。事实上，代谢与转录和翻译机制的相互作用显着影响疾病的结果。然而，代谢途径控制分辨率的精确机制尚未建立。 正在进行的工作表明，局部缺氧（缺氧）在炎症显着影响组织的代谢需求。在正在进行的工作中，我们一直专注于定义转录因子缺氧诱导因子（HIF）如何塑造炎症病变的微环境。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控制屏障功能的易处理的HIF特异性靶点，特别是当它们与快速能量利用（例如肌酸激酶和磷酸肌酸的产生）相关时。 在这个建议中，我们将定义上皮代谢如何塑造胃肠道炎症过程中的微环境。我们的项目将特别强调炎症反应的早期事件。三个协同的具体目标是针对测试的假设，炎症相关的变化内的微环境建立代谢控制炎症解决。在目标1中，我们将定义肌酸代谢在急性结肠炎症中的功能意义。目的2将集中在急性炎症细胞的贡献，代谢的微环境控制在体外和体内。具体目标3将阐明上皮HIF-1和HIF-2特异性代谢物的作用，并扩展这些发现，以了解这些变化如何在慢性炎症中转化。 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，并且这项工作的扩展将导致实验治疗的靶点。