Metabolic Regulation of Mucosal Inflammation

炎症性肠病(IBD)，包括克罗恩病和溃疡性结肠炎， 西方世界最令人衰弱的炎症性疾病之一。据估计，超过1.5 数以百万计的美国人患有IBD，许多人群的发病率都在上升。在军队中 退伍军人，IBD是所有疾病中住院率最高的疾病之一。此外，与IBD相关的癌症 在一些退伍军人中，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 上皮细胞和白细胞之间，包括中性粒细胞、巨噬细胞和树突状细胞。我们的 正在进行的研究表明，迁移的中性粒细胞建立了对 炎性病变内的代谢。在这种条件下，上皮细胞有能力 动态控制粘膜分辨率，并以高保真的方式进行。 直到最近才认识到，炎症相关的新陈代谢变化是 炎症反应。事实上，新陈代谢与转录和翻译的相互作用 机械设备对疾病结果有很大影响。代谢途径的精确机制 然而，控制决议尚未确定。 正在进行的研究表明，炎症过程中局部的氧气耗竭(缺氧) 显著影响组织的新陈代谢需求。在正在进行的工作中，我们将重点放在界定 转录因子缺氧诱导因子(HIF)如何影响炎症的微环境 损伤。使用全球染色质免疫沉淀启动子阵列(芯片-芯片)与详细的 基于核磁共振的代谢组学，我们已经在肠上皮细胞中确定了易处理的HIF特异性靶点 控制屏障功能，特别是当它们与快速能量利用有关时(例如，肌酸激酶和 磷酸肌酸的生成)。 在这项提案中，我们将定义上皮新陈代谢如何塑造在 胃肠道发炎。我们的项目将特别强调早期的炎症性事件 回应。三个协同作用的具体目标旨在检验与炎症相关的假设 微环境中的变化建立了新陈代谢控制和炎症消退。在目标1中，我们将 明确肌酸代谢在急性结肠炎中的功能意义。目标2将专注于 急性炎症细胞在体内和体外代谢微环境调控中的作用。特定的 目标3将阐明上皮HIF-1和HIF-2特定代谢物的作用，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对粘膜固有调节的新见解。 炎症消解和这项工作的扩展将导致实验疗法的靶点。

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.