Understanding the Role of a Long Noncoding RNA in Celiac Disease

了解长非编码 RNA 在乳糜泻中的作用

• 批准号: 9336894
• 负责人: Sankar Ghosh
• 金额: $ 36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336894
• 关键词: Affect; Binding; Binding Proteins; Biochemical; Biochemical Genetics; Bioinformatics; Biological; Biological Markers; Biopsy; Biotinylation; Celiac Disease; Chromosomes, Human, Pair 2; Cultured Cells; Diagnosis; Diet; Disease; Down-Regulation; Drug or chemical Tissue Distribution; Early Diagnosis; Gene Expression; Genes; Genetic; Genetic Transcription; Gluten; Human; Human Genome; Immunologic Receptors; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Ingestion; Intestinal Diseases; Intestines; Laboratories; Lead; Maintenance; Malabsorption Syndromes; Maps; Mass Spectrum Analysis; Mediating; Methods; Molecular; Molecular Biology; Mucositis; Mucous Membrane; Normal Cell; Nursing Faculty; Nutrient; Pathway interactions; Patients; Play; Population; Predisposition; Process; Production; Protein Biosynthesis; Proteins; Reaction; Regulation; Regulatory Element; Reporting; Research; Role; Sampling; Single Nucleotide Polymorphism; Site; Specificity; Stimulus; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Time; Untranslated RNA; Variant; cell type; cytokine; decapping enzyme; genome wide association study; genomic profiles; human disease; immunoreaction; in vivo Model; inflammatory marker; intestinal homeostasis; new therapeutic target; novel; novel marker; public health relevance; response; targeted treatment; tool; transcription factor

DESCRIPTION (provided by applicant): Celiac disease is an intestinal inflammatory disorder caused by an immune reaction to the ingestion of gluten. This reaction can produce intestinal inflammation, which over time, can lead to damage of the intestinal lining and malabsorption of nutrients. Although intolerance to dietary gluten and known genetic factors have been implicated in susceptibility to celiac disease, the exact causes of the disease are unknown. It has been reported that the inducible transcription factor, NF-κB, which is a key regulator of many inflammatory mediators, is activated in the inflamed mucosa of celiac patients, and is furthermore involved in the progression of mucosal inflammation in various intestinal diseases. We have identified a novel regulatory element, long noncoding RNA (lncRNA) 13 (lnc13), which modulates NF-κB-dependent gene expression in cultured cells, and importantly, is downregulated in celiac patient biopsies. This lncRNA also contains a single nucleotide polymorphism (SNP) associated with both celiac disease and inflammatory bowel disease (IBD) as assessed by genome-wide association studies (GWAS). We believe that lnc13 plays an important role in the maintenance of intestinal homeostasis, and that dysregulation of lnc13 expression or function might affect NF-κB dependent inflammatory processes in the intestine. To better understand the role of lnc13 in NF-κB regulation and its implications for celiac disease, we propose 3 specific aims. In Aim 1, we will further characterize human lnc13, and will generate a lnc13- related genomic profile of celiac patients in order to establish lnc13 and its regulators as novel biomarkers for diagnosis or novel targets for therapeutic intervention. In Aim 2, we will define how lnc13 is differentially regulated during a state of inflammation, leading to increased expression of pro-inflammatory mediators. Finally, in Aim 3, we will both determine the mechanisms by which lnc13 regulates NF-κB-dependent inflammatory gene expression, as well as examine the contribution of lnc13 to progression of inflammation in in vivo models of intestinal inflammatory disease.

描述(申请人提供)：乳糜泻是一种肠道炎症性疾病，由摄入面筋引起的免疫反应引起。这种反应会产生肠道炎症，随着时间的推移，可能会导致肠壁受损和营养吸收不良。虽然对膳食面筋的不耐受和已知的遗传因素与乳糜泻的易感性有关，但这种疾病的确切原因尚不清楚。已有研究表明，可诱导转录因子NF-κB是许多炎症介质的关键调节因子，在患者的炎症黏膜中被激活，并进一步参与了多种肠道疾病的黏膜炎症过程。我们已经确定了一种新的调控元件，长非编码RNA(LncRNA)13(LNC13)，它在培养细胞中调节依赖于NF-κB的基因表达，重要的是，在腹部患者的活检组织中下调。该LncRNA还包含与乳糜泻和炎症性肠病(IBD)相关的单核苷酸多态(SNP)，这是由全基因组关联研究(GWAS)评估的。我们认为，LNC13在维持肠道内环境平衡中起着重要作用，LNC13表达或功能失调可能会影响肠组织中依赖于NF-κB的炎症过程。为了更好地了解LNC13在NF-κB调节中的作用及其对乳糜泻的影响， 我们提出了三个具体目标。在目标1中，我们将进一步描述人类LNC13的特征，并将建立与LNC13相关的腹腔患者的基因组图谱，以建立LNC13及其调节因子作为新的诊断生物标志物或治疗干预的新靶点。在目标2中，我们将定义lnc13在炎症状态下如何差异调节，导致促炎介质表达增加。最后，在目标3中，我们将在肠道炎症性疾病的活体模型中，确定LNC13调节NF-κB依赖的炎症基因表达的机制，以及LNC13在炎症进展中的作用。