Metabolic Regulation of Mucosal Inflammation

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，许多人的发病率正在上升 人口。最近对10万多名军人进行的一项研究估计， IBD的发病率是非服役成员的2-10倍，两者之间存在显著的相关性 IBD发病率与生活应激源的数量之间的关系。IBD的确切病因尚不清楚。 我们的兴趣集中在组织中与炎症相关的变化的识别上 炎症性肠病发作期间的代谢。这些研究的基础是观察到的活跃的 IBD的肠道炎症的特征是组织代谢的显著变化，可以 从根本上影响细胞和组织的功能。在这种条件下，上皮细胞 有能力动态控制粘膜分辨率，并在很大程度上 富达。然而，代谢途径控制分辨率的确切机制有 目前尚不清楚。我们正在进行的工作揭示了局部的氧气耗竭(缺氧) 炎症期间会显著影响组织的新陈代谢需求。在正在进行的工作中， 我们利用全球染色质免疫沉淀启动子阵列(芯片-芯片)联合 用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。这些研究已经确定了肌酸和腺苷 能量中间体在上皮屏障调节中的检查点代谢产物 发炎。 在这个提案中，我们将定义上皮新陈代谢如何塑造粘膜组织。 炎症期间的环境。三个协同的具体目标旨在测试 假设组织环境内的炎症相关变化建立 通过促进粘膜屏障功能对炎症消退的代谢控制。在……里面 目标1将集中在确定腺苷酸能量代谢和AMP激酶激活在 粘膜内的屏障调节。目标2将阐明肌酸转运在心肌细胞中的功能。 上皮屏障功能的调节。具体目标3将阐明肌酸转运的作用 体内腺苷能量代谢在屏障调节和伤口愈合中的作用。这是我们的希望 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治疗学的目标。

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.