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IDO1 IN THE HUMAN GUT EPITHELIUM

人类肠道上皮中的 IDO1

基本信息

批准号：
8791898
负责人：
MATTHEW AARON CIORBA
金额：
$ 7.6万
依托单位：
WASHINGTON UNIVERSITY
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：
2014-01-15 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791898
关键词：
Agonist Animal Model B Cell Proliferation Biopsy Cancer cell line Catabolism Cell Culture System Cell Culture Techniques Cell Line Cell Proliferation Cells Cellular biology Chronic Chronic Disease Clinical Clinical Trials Code Colitis Colon Colon Carcinoma Crohn&apos s disease Culture Techniques Data Dioxygenases Disease Enterocytes Environment Enzymes Epithelial Epithelial Cells Epithelium Essential Amino Acids Experimental Models Exposure to Functional disorder Funding Genes Genetic Polymorphism Genetic Transcription Genotype Goals Goblet Cells Healed Health Human Immune Tolerance In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interferons Intestines Knowledge Kynurenine Lead Malignant - descriptor Malignant Neoplasms Mediating Methods Modeling Morbidity - disease rate Mus Pathology Pathway interactions Patients Pattern Phenotype Population Proteins Regulation Sampling Serum Shapes Signal Transduction Small Intestines Source Specialized Epithelial Cell Stem cells Stimulus Stress Surface System TNF gene Techniques Testing Time Toll-like receptors Translating Tryptophan Ulcerative Colitis Variant Work cell type colitis associated cancer cytokine direct application disorder risk gastrointestinal gastrointestinal epithelium gene environment interaction healing human disease indoleamine inhibitor/antagonist innovation insight interest mortality novel pathogen protein expression receptor expression repository response risk variant small hairpin RNA therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): The specialized epithelial cells lining the gut's mucosal surface mediate important functions in digestive health and disease. Epithelial cell dysfunction can cause or contribute to disease states such as colon cancer and human inflammatory bowel disease (IBD: Crohn's disease and ulcerative colitis). Together gut epithelial related diseases cause substantial morbidity and mortality in the US. Indoleamine 2,3 dioxygenase (IDO1), an enzyme that catabolizes the essential amino acid tryptophan to kynurenine, is one of the most highly upregulated genes in human IBD and animal models of colitis. Over the current K08 funding period we have determined using animal models and fixed IBD patient samples that colon epithelial cells (CECs) upregulate IDO1 in human IBD and in mouse colitis models. Though it has been proposed that IDO's main function in the gut it to promote immune tolerance, our data demonstrate that IDO1 activity also correlates with epithelial proliferation in animal models of colitis and colitis-associated cancer. Though experimental models and cancer cell lines provide valuable insights, these findings often do not translate to human disease. In this proposal we will use a novel epithelial cell culture technique to study the function and regulation of IDO1 in human gut epithelial cells. We hypothesize that "Cell type specific induction and regulation of IDO1 mediates a cell-autonomous proliferative response in native human intestinal epithelial cells through kynurenine metabolites." IDO1 is an important therapeutic target in diseases of chronic inflammation and malignancy. IDO1 inhibitors as well as agents that induce IDO1 are moving to clinical trial, thus it will be important to understand the implications of modifying IDO1 activity in the gut epithelium. The overall goal of this RO3 is to establish the system's utility as a new tool for the study of IDO1 in human gut epithelial cells. Preliminary data will be generated to support an RO1 application directed at understanding the broader functions of epithelial IDO1 as relates to human IBD and colon malignancy.

描述(申请人提供)：肠道粘膜表面的特殊上皮细胞在消化健康和疾病中起重要作用。上皮细胞功能障碍可导致或促成结肠癌和人类炎症性肠病(IBD：克罗恩病和溃疡性结肠炎)等疾病状态。在美国，与肠道上皮相关的疾病一起导致了相当大的发病率和死亡率。吲哚胺2，3双加氧酶(IDO1)是一种将必需氨基酸色氨酸分解为犬尿氨酸的酶，是人类IBD和动物结肠炎模型中表达最高的基因之一。在当前的K08资助期内，我们使用动物模型和固定的IBD患者样本确定，在人IBD和小鼠结肠炎模型中，结肠上皮细胞(CEC)上调IDO1。虽然有人认为IDO在肠道中的主要功能是促进免疫耐受，但我们的数据表明，在结肠炎和结肠炎相关癌症的动物模型中，IDO1的活性也与上皮细胞的增殖有关。尽管实验模型和癌细胞系提供了有价值的见解，但这些发现通常不会转化为人类疾病。在这项建议中，我们将使用一种新的上皮细胞培养技术来研究IDO1在人类肠道上皮细胞中的功能和调节。我们假设“IDO1的细胞类型特异性诱导和调节通过犬尿氨酸代谢产物在天然人类肠上皮细胞中介导细胞自主的增殖反应。”IDO1是治疗慢性炎症和恶性肿瘤的重要靶点。IDO1抑制剂以及诱导IDO1的药物正在进入临床试验，因此了解修改肠上皮中IDO1活性的含义将是重要的。该RO3的总体目标是建立该系统作为研究人类肠道上皮细胞中IDO1的新工具的效用。将产生初步数据以支持RO1应用，旨在了解上皮IDO1与人类IBD和结肠恶性肿瘤相关的更广泛的功能。