Mechanisms associated with flares and remission in colitis

结肠炎发作和缓解的相关机制

• 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
• 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' 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

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

总结 克罗恩病（CD）和溃疡性结肠炎（UC）是两种不同的炎症性肠病表型 IBD影响约150万美国人，每年诊断出> 30，000例新病例。他们都是 以无症状缓解期被症状性疾病发作中断为特征，或 加重虽然其确切原因尚不清楚，但IBD似乎是由于环境因素的组合 因素和遗传易感性。然而，到目前为止，还不清楚缺陷基因是如何改变的， 环境相互作用引起结肠炎，并促进复发和缓解周期的发展。到 为了更好地理解这些过程，我们创建了一种新的动物模型（R23 FR小鼠）， IL-23是一种与结肠炎相关的基因，它在免疫活性小鼠的肠道中有条件地表达。 小鼠IL-23表达触发依赖于微生物群和饮食的结肠炎的发展， 这与人类疾病有着惊人的相似之处，疾病周期是活动性的（复发/爆发），然后是 缓解。本申请的主要目的是研究IL-23和微生物群如何相互作用。 以促进结肠炎和发展周期的耀斑和缓解。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 在目标2中，我们将定义微生物群如何影响R23 FR中结肠炎的发展 在目标3中，我们将定义淋巴细胞如何促进发作和缓解