Mechanisms associated with flares and remission in colitis

结肠炎发作和缓解的相关机制

基本信息

批准号：
10297538
负责人：
SERGIO A. LIRA
金额：
$ 71.94万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297538
关键词：
Affect Animals Antigens Autoimmune Diseases Bacteria Beverages Binding Biology CD4 Positive T Lymphocytes Candy Cecum Cells Chemicals Cherry - dietary Child Citrobacter rodentium Clinical Colitis Consumption Cosmetics Coupled Data Dendritic Cells Developing Countries Development Diet Diet Habits Disease Disease remission Environmental Risk Factor Etiology Exposure to Flare Food Food Coloring Agents Generations Genetic Genetic study Haptens Hormones Human Hydration status Immune Immune response Immune system In Vitro Incidence Incubated Individual Infection Inflammatory Inflammatory Bowel Diseases Injections Intestines Lead Life Link Medicine Modern Medicine Mus Myeloid Cells Naphthols Pharmaceutical Preparations Play Prevention Production Property Proteins Regulatory T-Lymphocyte Research Project Grants Role Signal Pathway Sum T-Lymphocyte Testing Tissues Wild Type Mouse Work base cytokine dietary experimental study inflammatory disease of the intestine interest interleukin-23 microbiota response soft drink

项目摘要

Summary Inflammatory bowel diseases (IBD) affect millions of individuals worldwide and its incidence is increasing. Both genetic and environmental factors appear to play a role in IBD development. Genetic studies in humans have linked the interleukin-23 (IL-23) signaling pathway with IBD, but the environmental factors contributing to disease, have remained elusive. The rising incidence of worldwide IBD has been associated with westernization of dietary habits in developing countries, however there is little scientific evidence to support causality. In this application we will examine the role of a particular group of dietary additives, namely food colorants, to development of colitis. We have now discovered that the food colorant Red 40, also known as Allura Red AC, promotes colitis in mice that conditionally express low levels of IL-23 (referred to as R23FR mice), but not in wild type mice. Red 40 is the most abundant food colorant in the world, with annual production exceeding 2.3 million kg. It is widely used in as red colorant in soft drinks, cherry flavored products, candy, dairy, drugs, and cosmetics. Of interest, the Red 40-containing beverages, Kool-Aid and the hydrating solution Pedialyte Cherry can also cause colitis in R23FR mice. Red 40-induced colitis in R23FR mice requires the microbiota and CD4+ T cells. Based on these and other results presented here, we formulate a central hypothesis that the Red 40 or its metabolites haptenize bacterial or endogenous proteins to generate tolerance in wild type mice, or colitis in mice in which IL-23 expression is dysregulated. We will study in this proposal the mechanisms involved in generation and prevention of these responses. Specifically, we will define: 1) if Red 40 and its metabolite ANSA are haptens; 2) how Red 40 induces tolerance in control mice; and 3) if Red 40 or ANSA-specific T cells are generated in R23FR mice

概括炎症性肠病 (IBD) 影响着全世界数百万人，并且其发病率正在增加。两个都遗传和环境因素似乎在 IBD 的发展中发挥着作用。人类基因研究已白细胞介素 23 (IL-23) 信号通路与 IBD 相关，但环境因素会导致疾病，仍然难以捉摸。全球 IBD 发病率上升与饮食西化有关发展中国家的习惯，但几乎没有科学证据支持因果关系。在这个应用程序中我们将研究一组特定的膳食添加剂（即食品着色剂）在开发结肠炎。我们现在发现食品着色剂 Red 40（也称为 Allura Red AC）会促进结肠炎在条件性表达低水平 IL-23 的小鼠（称为 R23FR 小鼠）中，但在野生型小鼠中则不然。红色的 40是世界上最丰富的食品着色剂，年产量超过230万公斤。它被广泛用作软饮料、樱桃味产品、糖果、乳制品、药品和化妆品中的红色着色剂。感兴趣的是，含有 Red 40 的饮料、Kool-Aid 和保湿液 Pedialyte Cherry 也会导致结肠炎 R23FR 小鼠。 R23FR 小鼠中 Red 40 诱导的结肠炎需要微生物群和 CD4+ T 细胞。基于这些和这里提出的其他结果，我们提出了一个中心假设，即 Red 40 或其代谢物半抗原化细菌或内源性蛋白质在野生型小鼠中产生耐受性，或在小鼠中产生结肠炎，其中 IL-23 表达失调。我们将在本提案中研究涉及产生和预防的机制这些回应。具体来说，我们将定义： 1) Red 40 及其代谢物 ANSA 是否为半抗原； 2）有多红 40 诱导对照小鼠耐受； 3) R23FR 小鼠中是否产生 Red 40 或 ANSA 特异性 T 细胞