Characterization and Targeting of MiR-24 Network in Colitis

结肠炎中 MiR-24 网络的表征和靶向

• 批准号: 9982318
• 负责人: CHARALABOS POTHOULAKIS
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982318
• 关键词: 3' Untranslated Regions; Acute; Address; Affect; Binding; Binding Sites; Biopsy; Chemicals; Chronic; Colitis; Colon; Colorectal Cancer; Computer Analysis; Crohn' s disease; Data; Disease; Disease remission; Effectiveness; Epithelial; Epithelial Cells; Epithelium; Etiology; Experimental Models; Feedback; Functional disorder; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Gene Targeting; Genes; Genetic Transcription; HNF4A gene; Human; IL6 gene; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-6; Intestinal permeability; Intracolonic; Irritable Bowel Syndrome; Matrix Metalloproteinases; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Analysis; Mus; Names; PPAR gamma; Pathogenesis; Pathologic; Pathway interactions; Patients; Permeability; Play; Public Health; Regulation; Regulator Genes; Role; STAT3 gene; Signal Pathway; Signal Transduction; T-Lymphocyte; TNF gene; Therapeutic; Tissues; Ulcerative Colitis; United States; Untranslated RNA; base; clinically significant; cohort; collagenase 3; in vivo; inflammatory disease of the intestine; inhibitor/antagonist; insight; mouse model; novel; promoter; response; transcription factor

PROJECT SUMMARY MicroRNAs are small non-coding RNA molecules that have been implicated in the pathogenesis of different human inflammatory diseases. Recent evidence indicates that manipulation of microRNA expression could have therapeutic potential in inflammatory diseases of different etiologies. We and others have identified that microRNAs are deregulated in Inflammatory Bowel Disease (IBD); however their role and functional importance in IBD pathophysiology is not well understood. Our preliminary evidence revealed that miR-24 expression is specifically up-regulated in colonic biopsies from 2 cohorts of ulcerative colitis (UC), but not Crohn's disease (CD) patients or patients with other GI diseases (irritable bowel syndrome, colorectal cancer). Furthermore, miR-24 expression is higher in colonic biopsies from UC patients with active disease relative to UC patients in remission. Although several microRNAs have been found to be deregulated in different gastrointestinal (GI) diseases, our results demonstrate that miR-24 is specifically deregulated in UC, suggesting an important role in UC pathogenesis. A key question in the microRNA field is the identification of their direct gene targets. Here, we have followed an unbiased integrative computational and molecular analysis and found that miR-24 is potentially involved in UC pathogenesis by regulating a gene network consisting of an inflammatory (HFN4A-PPARγ-NF-κB) circuit by targeting directly HNFA, and an intestinal permeability control mechanism, by modulating directly claudin-7, which affects the ERK and MMP signaling pathways. Thus, these data suggest that miR-24 regulates inflammation and epithelial permeability, both key aspects of UC pathogenesis. On the other hand, suppression of HNF4A and/or claudin-7 reinforced miR-24 increased expression, suggesting the presence of a feedback loop network. This is the first evidence describing a microRNA to act as a rheostat of the inflammatory response and intestinal permeability, through regulation of a feedback loop network. Here, we will examine the novel hypothesis that the miR-24 network plays an important role in UC pathophysiology by regulating inflammatory and intestinal permeability mechanisms. Based on strong preliminary findings the following aims will address this overall hypothesis. Aim 1 will evaluate the role of miR-24 – HNF4A network on controlling the inflammatory responses in UC. Aim 2 will characterize the molecular mechanism of miR-24 on intestinal epithelial permeability. Use of human UC patient tissues will confirm the UC relevance of the findings in aims 1 and 2. Aim 3 will examine the therapeutic potential of miR- 24 inhibition, by administering a novel chemically-stable miR-24 inhibitor (UCDI-1), in mouse models of experimental colitis (in vivo) and in freshly isolated colonic explants from UC patients (ex vivo). Understanding the miR-24 molecular network will not only provide novel insights on the role of miR-24 in UC pathophysiology, but it may also determine the therapeutic potential of miR-24 inhibition by UCDI-1 in UC.

项目总结