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（由申请人提供）：乳糜泻是一种肠道炎症性疾病，由摄入麸质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，会导致肠道内壁受损和营养吸收不良。虽然对饮食麸质不耐受和已知的遗传因素与乳糜泻的易感性有关，但该疾病的确切原因尚不清楚。据报道，诱导转录因子NF-κB是多种炎症介质的关键调节因子，在乳糜泻患者的炎症黏膜中被激活，并进一步参与各种肠道疾病粘膜炎症的进展。我们已经发现了一种新的调控元件，长链非编码RNA (lncRNA) 13 (lnc13)，它在培养细胞中调节NF-κ b依赖性基因的表达，重要的是，在乳糜泻患者活检中被下调。通过全基因组关联研究（GWAS）评估，该lncRNA还含有与乳糜泻和炎症性肠病（IBD）相关的单核苷酸多态性（SNP）。我们认为lnc13在维持肠道内稳态中起着重要作用，而lnc13表达或功能的失调可能会影响肠道中NF-κB依赖性炎症过程。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，