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：
9922284
负责人：
SERGIO A. LIRA
金额：
$ 38.14万
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922284
关键词：
Adoptive Cell Transfers Affect American Animal Model Animals B-Lymphocytes CRISPR/Cas technology Cecum Cells Colitis Crohn&apos s disease Data Dendritic Cells Development Diagnosis Diet Dietary Factors Disease Disease remission Environment Environmental Risk Factor Epithelial Cells Flare Genes Genetic Genetic Predisposition to Disease Human Immunocompetent Immunoglobulin A Immunologics Inflammatory Bowel Diseases Interruption Intestines Knowledge Lymphocyte Lymphocyte Count Metabolic Methods MicroRNAs Modeling Mus Mutant Strains Mice Pattern Phenotype Process Regulatory T-Lymphocyte Relapse Reporter Shapes T-Cell Depletion T-Lymphocyte Subsets Testing Transgenic Mice Ulcerative Colitis gut microbiota healing human disease in vivo insight interleukin-22 interleukin-23 macrophage metabolome microbial microbiome microbiota new therapeutic target novel transcriptome γδ T cells

项目摘要

Summary Crohn's disease (CD) and ulcerative colitis (UC) are two distinct phenotypic patterns of inflammatory bowel disease (IBD) affecting ~1.5 million Americans, with >30,000 new cases diagnosed annually. They are both characterized by periods of asymptomatic remission interrupted by episodes of symptomatic disease flares or exacerbations. While its exact cause is unknown, IBD seems to be due to a combination of environmental factors and genetic predisposition. However, to date, it is unclear how faulty genes and the changed environment interact to cause colitis and to promote development of cycles of flares and remissions. To contribute to a better understanding of these processes we created a novel animal model (R23FR mice), in which a gene associated with colitis, IL-23 is conditionally expressed in the intestine of immune-competent mice. IL-23 expression triggers development of a colitis that is dependent on the microbiota and the diet, and that has a striking resemblance to human disease, with cycles of active disease (relapse/flares) followed by remission. The main objective of this application is to investigate how IL-23 and the microbiota interact to promote colitis and the development of cycles of flares and remission. Knowledge obtained from these studies is likely to open new directions for therapy. In Aim 1 we will define the mechanisms triggered by IL-23 that contribute to colitis; in Aim 2 we will define how the microbiota affects the development of colitis in R23FR mice; and in Aim 3 we will define how lymphocytes contribute to flares and remission

概括克罗恩病 (CD) 和溃疡性结肠炎 (UC) 是炎症性肠病的两种不同表型模式疾病（IBD）影响约 150 万美国人，每年诊断出超过 30,000 例新病例。他们都是其特征是无症状缓解期被有症状的疾病发作打断或病情加重。虽然其确切原因尚不清楚，但 IBD 似乎是由环境因素共同造成的。因素和遗传倾向。然而，迄今为止，尚不清楚缺陷基因和改变是如何发生的。环境相互作用导致结肠炎并促进发作和缓解周期的发展。到为了更好地理解这些过程，我们创建了一种新型动物模型（R23FR 小鼠）， IL-23 是一种与结肠炎相关的基因，在免疫功能正常的肠道中条件性表达老鼠。 IL-23 表达会引发依赖于微生物群和饮食的结肠炎的发展，并且这与人类疾病有着惊人的相似之处，具有活动性疾病（复发/发作）的周期，然后是缓解。该应用的主要目的是研究 IL-23 和微生物群如何相互作用促进结肠炎以及发作和缓解周期的发展。从这些获得的知识研究可能会为治疗开辟新的方向。在目标 1 中，我们将定义 IL-23 触发的机制导致结肠炎；在目标 2 中，我们将定义微生物群如何影响 R23FR 中结肠炎的发展老鼠；在目标 3 中，我们将定义淋巴细胞如何促进发作和缓解