IDO1 IN THE HUMAN GUT EPITHELIUM

描述（申请人提供）：肠道粘膜表面的特化上皮细胞在消化系统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疾病状态，如结肠癌和人类炎症性肠病（IBD：克罗恩病和溃疡性结肠炎）。在美国，肠道上皮相关疾病导致了大量的发病率和死亡率。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和结肠炎动物模型中表达上调最多的基因之一。在目前的K08资助期内，我们已经通过动物模型和固定的IBD患者样本确定，结肠上皮细胞（CECs）在人类IBD和小鼠结肠炎模型中上调IDO1。虽然已经提出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活性也与上皮细胞增殖有关。虽然实验模型和癌细胞系提供了有价值的见解，但这些发现往往不能转化为人类疾病。在本研究中，我们将使用一种新的上皮细胞培养技术来研究IDO1在人肠道上皮细胞中的功能和调控。我们假设“细胞类型特异性诱导和调节IDO1通过犬尿氨酸代谢物介导天然人肠上皮细胞的细胞自主增殖反应。”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的药物正在进入临床试验阶段，因此了解改变肠道上皮中IDO1活性的意义将是很重要的。本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的应用，旨在了解上皮IDO1与人类IBD和结肠恶性肿瘤相关的更广泛功能。

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.