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Metabolic Regulation of Mucosal Inflammation

粘膜炎症的代谢调节

基本信息

批准号：
10585958
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
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585958
关键词：
Actins Acute Address Adherens Junction American Antigens Apical Back Bacteria Brain Cells Cellular Metabolic Process Colitis Colon Complex Creatine Creatine Kinase Crohn&apos s disease Cytoskeleton Defect Development Digestive System Disorders Disease Energy Metabolism Environment Enzymes Epithelial Cells Epithelium Etiology Family Flare Flow Cytometry Gastrointestinal Diseases Generations Hospitalization Human Immune Immune response Impairment In Vitro Incidence Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune Response Invaded Investigational Therapies Life Link Location Maintenance Measures Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Molds Molecular Mucositis Mucous Membrane Mus Mutant Strains Mice NADH Natural Immunity Nutrient Oxidation-Reduction Pathway interactions Peripheral Blood Mononuclear Cell Phosphocreatine Population Predisposition Process Production Protein Isoforms Recombinants Regulation Resolution Role Severity of illness Signal Transduction Site Splenocyte Stress Supplementation T-Lymphocyte TNF gene Testing Therapeutic Agents Tight Junctions Tissues Translating Tryptophan Metabolism Pathway Ulcerative Colitis Western World Work adenylate attenuation cell type design falls gut inflammation healing hospitalization rates human model in vivo inorganic phosphate insight interest intestinal epithelium kinase inhibitor knock-down loss of function metabolomics microbial products military patient military service military veteran mouse model murine colitis novel novel therapeutics readmission rates response service member stressor

项目摘要

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.

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，更多 300多万美国人患有IBD，许多人群的发病率都在上升。一个最近对10万多名军人进行的一项研究估计，IBD的发病率为是非服役成员的2-10倍，与IBD发病率之间存在显著关系以及生活压力源的数量。IBD的确切病因目前尚不清楚。我们的兴趣集中在组织中与炎症相关的变化的识别上活动性炎症爆发时的代谢。我们正在进行的研究是建立在观察到活动性肠炎的特征是组织明显移位新陈代谢可以从根本上重要地影响细胞和组织的功能。在……下面在这种情况下，上皮细胞具有动态控制粘膜分辨率和要以高度的保真度做到这一点。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确凿地揭示了在活动性炎症期间能量利用受到影响，肌酸和它的相关的肌酸激酶(CK)家族是高能穿梭的基础在三磷酸腺苷生成部位之间以磷酸肌酸形式的磷酸盐。此外，我们有研究表明，双突变小鼠缺乏脑和线粒体CK亚型(称为根据多种疾病的衡量，CKO)更容易患急性结肠炎参数。除了屏障功能受损外，CK dKO小鼠还表现出炎症性缺陷几乎不存在的结肠型干扰素水平突显了这种反应。在这项提案中，我们将定义肌酸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上皮细胞和免疫细胞内CK的表达和活性是基本的在黏膜的炎症消退反应中。目标1将阐明肌酸激酶(S)如何最终影响炎症活动期间的组织新陈代谢。目标2将定义规则 CK酶对干扰素的抑制作用。特指目标3将阐明干扰素与肌酸激酶的关系代谢在调节肠道炎症中的作用。我们希望这些结果将揭示对粘膜炎症消退内在调节及其延伸的新见解这项工作将导致实验疗法的目标。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Allopurinol Disrupts Purine Metabolism to Increase Damage in Experimental Colitis.

别嘌呤醇会扰乱嘌呤代谢，增加对实验性结肠炎的损害。

DOI：
10.3390/cells13050373
发表时间：
2024
期刊：
Cells
影响因子：
6
作者：
Worledge,CoreyS;Kostelecky,RachaelE;Zhou,Liheng;Bhagavatula,Geetha;Colgan,SeanP;Lee,JScott
通讯作者：
Lee,JScott

Disruption of monocyte-macrophage differentiation and trafficking by a heme analog during active inflammation.

DOI：
10.1038/s41385-021-00474-8
发表时间：
2022-03
期刊：
Mucosal immunology
影响因子：
8
作者：
Schaefer REM;Callahan RC;Atif SM;Orlicky DJ;Cartwright IM;Fontenot AP;Colgan SP;Onyiah JC
通讯作者：
Onyiah JC

(E)-3-Bromo-N'-(5-bromo-2-hydroxy-benzyl-idene)benzohydrazide.

(E)-3-溴-N-(5-溴-2-羟基-亚苄基)苯甲酰肼。