IDO1 IN THE HUMAN GUT EPITHELIUM

人类肠道上皮中的 IDO1

基本信息

批准号：
8624339
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/8624339
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 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 Techniques Testing Time Toll-like receptors Translating Tryptophan Tumor Necrosis Factor-alpha 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（由申请人提供）：肠粘膜表面内衬的专门上皮细胞介导了消化健康和疾病中的重要功能。上皮细胞功能障碍可能导致或导致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。肠道上皮相关疾病在美国引起了大量的发病率和死亡率。吲哚胺2,3二氧酶（IDO1）是一种将必需氨基酸色氨酸与kynurenine分解的酶，是人IBD中最高度上调的基因之一和结肠炎动物模型。在当前的K08融资期内，我们使用动物模型和固定的IBD患者样品确定了结肠上皮细胞（CEC）在人IBD和小鼠结肠炎模型中上调IDO1。尽管已经提出IDO在肠道中的主要功能促进免疫耐受性，但我们的数据表明，IDO1活性也与结肠炎和结肠炎相关癌症的动物模型中的上皮增殖有关。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。在此提案中，我们将使用一种新型的上皮细胞培养技术来研究人肠上皮细胞中IDO1的功能和调节。我们假设“ IDO1的细胞类型特异性诱导和调节可以通过kynurenine代谢物中介导人类肠道上皮细胞中细胞自主的增殖反应”。 IDO1是慢性炎症和恶性肿瘤疾病的重要治疗靶点。 IDO1抑制剂以及诱导IDO1的药物正在进行临床试验，因此了解修改肠道上皮中IDO1活性的含义非常重要。该RO3的总体目标是将系统的效用确定为研究人类肠道上皮细胞中IDO1的新工具。将生成初步数据，以支持针对人类IBD和结肠恶性肿瘤的上皮IDO1的更广泛功能的RO1应用程序。