microRNA-10a Regulation of Inflammatory Bowel Diseases

microRNA-10a 对炎症性肠病的调节

• 批准号: 8631732
• 负责人: Yingzi Cong
• 金额: $ 33.6万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631732
• 关键词: Address; Animal Model; Antigens; Attenuated; Automobile Driving; Bacteria; Binding; Biological Preservation; Biopsy; Cells; Colitis; Crohn' s disease; Data; Dendritic Cells; Dendritic cell activation; Development; Epithelial Cells; Flow Cytometry; Functional RNA; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Homeostasis; Human; Immune; Immune System Diseases; Immune system; Immunoprecipitation; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-12; Intestinal Mucosa; Intestines; Lamina Propria; Lead; Lesion; Ligands; Luc Gene; Mediating; MicroRNAs; Mus; Pathogenesis; Pathway interactions; Patients; Play; Population; Prevention; Process; Production; RNA; RNA-Induced Silencing Complex; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Reporter; Reporting; Role; System; T cell response; T-Cell Development; T-Lymphocyte; TNF gene; Testing; Time; Transfection; Transgenic Organisms; Ulcerative Colitis; Untranslated Regions; Western Blotting; cytokine; human disease; in vivo; inhibitor/antagonist; interleukin-23; knock-down; new therapeutic target; novel; overexpression; public health relevance; response; small hairpin RNA; small molecule

Abstract: MicroRNAs (miRNA), a class of small non-coding RNAs, are emerging as important regulators of gene expression in the immune system by functioning as endogenous inhibitors of translational processes by binding to the 3'-UTR of target genes. There is increasing evidence that miRNAs function as an effective system to regulate the magnitude of inflammatory responses and have been associated with the pathogenesis of various human diseases. We have established recently that miR-10a, conserved in both mouse and human spp, was highly expressed in intestine dendritic cells (DC), and negatively regulated by microbiota through the interaction of TLR-TLR ligands via the MyD88 pathway. We identified IL-12/IL-23p40, which is shared by IL-12 and IL-23, two important cytokines in the pathogenesis of inflammatory bowel disease, as a target gene of miR-10a, in that miR-10a directly bound to the 3'-UTR of the IL-12/IL-23p40 gene, and overexpression of miR-10a inhibited DC IL-12/IL-23p40 expression and production of IL-12 and IL-23. miR-10a expression was decreased in the inflamed intestinal lesions in mice with colitis, which was correlated with high levels of IL- 12 and IL-23, compared to that in normal mice. A recent report further demonstrated that miR-10a attenuated regulatory T cell (Treg) conversion into effector T cells and inhibited Th17 differentiation. In the present proposal, our preliminary data demonstrate that miR-10a expression is decreased in intestinal biopsies of patients with Crohn's disease (CD) and ulcerative colitis (UC), when compared to its expression in normal individuals, a finding that is indicative of the relevance of dysregulated miR-10a to human IBD. NFkB activation is elevated in IBD patients and localizes primarily in the intestines to lamina propria dendritic and epithelial cells. Overexpression of miR-10a suppresses DC expression of NFkB activation and TNFa production and inhibits colitis development in an animal model. In this project, we will investigate the regulatory targets of miR-10a in mucosal DC, and the mechanisms of how miR-10a expression regulates mucosal DC activation and function in response to microbiota. Lastly, we will test our hypothesis that DC expression of miR-10a shifts mucosal T cell responses to low levesl of Th1/Th17 and high levels of Treg, which leads to preservation of intestinal immune homeostasis and prevention of inflammatory bowel disease.

摘要： MicroRNA（miRNA）是一类小的非编码RNA，正在成为细胞增殖的重要调控因子。 作为翻译过程的内源性抑制剂在免疫系统中的基因表达 通过结合靶基因的3 '-UTR。越来越多的证据表明，miRNAs作为一种有效的 系统调节炎症反应的程度，并已与 各种人类疾病的发病机制。 我们最近已经确定，在小鼠和人类物种中均保守的miR-10a， 在肠树突状细胞（DC）中表达，并通过以下相互作用受到微生物群的负调节： TLR-TLR配体通过MyD 88途径。我们鉴定了IL-12/IL-23 p40，其由IL-12和IL-23共享， 在炎症性肠病发病机制中的两种重要细胞因子，作为miR-10a的靶基因， miR-10a与IL-12/IL-23 p40基因的3 '-UTR直接结合，miR-10a过表达 抑制DC IL-12/IL-23 p40的表达和IL-12和IL-23的产生。miR-10a的表达是 在结肠炎小鼠的炎症性肠道病变中减少，这与高水平的IL- 12和IL-23的表达。最近的一份报告进一步证明，miR-10a 减弱调节性T细胞（Treg）转化为效应T细胞并抑制Th 17分化。在 目前的建议，我们的初步数据表明，miR-10a的表达减少，在肠道， 克罗恩病（CD）和溃疡性结肠炎（UC）患者的活检组织，当与其表达 在正常个体中，这一发现表明失调的miR-10a与人IBD相关。 NFkB激活在IBD患者中升高，并且主要定位于肠固有层 树突状细胞和上皮细胞。miR-10a过表达抑制DC表达NF κ B活化， 在动物模型中TNF α产生和抑制结肠炎发展。在这个项目中，我们将调查 miR-10a在粘膜DC中的调控靶点，以及miR-10a表达如何调控的机制 粘膜DC激活和功能响应于微生物群。最后，我们将测试我们的假设，DC miR-10a的表达将粘膜T细胞应答转变为低水平的Th 1/Th 17和高水平的Treg， 从而保持肠道免疫稳态并预防炎症性肠病 疾病