Metabolic Regulation of Mucosal Inflammation

炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎，是一种常见的肠道疾病。 是西方世界最严重的炎症性疾病之一据估计， 超过300万美国人患有IBD，许多人群的发病率都在上升。一 最近对10万多名军人的研究估计，IBD的发病率为 2-10比非服务人员高出一倍，IBD发病率与 和生活压力源的数量。IBD的确切病因目前尚不清楚。 我们的兴趣集中在组织中炎症相关变化的识别上 在活动性炎症发作期间进行代谢。我们正在进行的研究是建立在 观察到活动性肠道炎症的特征在于组织的显著变化， 代谢，可以影响细胞和组织的功能，在根本上重要的方式。下 在这种情况下，上皮细胞具有动态控制粘膜消退的能力， 以高度的忠诚度这样做。代谢途径控制的精确机制 然而，决议尚未阐明。我们正在进行的工作最终揭示了 在活动性炎症期间能量利用受到损害，肌酸及其 相关的肌酸激酶（CK）家族的酶是基本的穿梭高能量 在ATP生成位点之间以磷酸肌酸形式存在的磷酸盐。而且我们 显示缺乏脑和线粒体CK亚型的双突变小鼠（称为 CK dKO）对急性结肠炎的敏感性显著增加， 参数除了屏障功能受损外，CK dKO小鼠还表现出有缺陷的炎症反应。 结肠IFN γ水平几乎不存在。 在这个建议中，我们将定义肌酸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 假设上皮细胞和免疫细胞内CK表达和活性是基本的 在粘膜的炎症消退反应中。目的1将阐明肌酸激酶（S） 最终影响活动性炎症期间的组织代谢。目标2将规定 IFN γ的CK酶活性。具体目标3将阐明IFN γ与CK之间的关系 在肠道炎症的调节代谢。我们希望这些结果能揭示 对粘膜炎症消退的先天性调节的新见解， 这项工作将为实验性治疗提供目标。

The Inflammatory Bowel Diseases (IBD), including Crohn’s disease and ulcerative colitis, are among the most debilitating inflammatory disorders of the western world. It is estimated that more than 3 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 currently unknown. Our interest is focused on the identification of inflammation-associated changes in tissue metabolsim during flares of active inflammation. Our ongoing studies are founded on the observation that active intestinal inflammation is characterized by significant shifts in tissue metabolism that can influence cell and tissue function in fundamentally important 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 conclusively revealed that energy utilization becomes compromised during active inflammation and that creatine and its associated creatine kinase (CK) family of enzymes are fundamental in shuttling of high energy phosphates in the form of phosphocreatine between sites of ATP generation. Moreover, we have shown that double-mutant mice lacking the brain and mitochondrial isoforms of CK (termed the CK dKO) are significantly more susceptible to acute colitis as measured by multiple disease parameters. In addition to impaired barrier function, CK dKO mice showed defective inflammatory responses underscored by nearly non-existent levels of colonic IFN. In this proposal, we will define how creatine metabolism molds the mucosal tissue environment during inflammation. Three synergistic specific aims are directed at testing the hypothesis that CK expression and activity within the epithelia and immune cells are fundamental in inflammatory resolution responses in the mucosa. Aim 1 will elucidate how creatine kinase(s) ultimately influence tissue metabolism during active inflammation. Aim 2 will define the regulation of IFN by CK enzymes. Specific Aim 3 will illuminate the relationship between IFN and CK metabolism in the regulation of intestinal 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.