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

基本信息

批准号：
9115578
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
项目类别：
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/9115578
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 Health Human Human Genome Immune 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 in vivo Model inflammatory marker intestinal homeostasis novel novel marker response targeted treatment tool transcription factor

项目摘要

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（由适用提供）：腹腔疾病是一种肠道炎症性疾病，是由于对面筋摄入的免疫反应引起的。随着时间的流逝，这种反应会产生肠道炎症，从而导致营养素的肠壁和吸收不良的损害。尽管对饮食面筋和已知遗传因素的摄入已被暗示，这是对腹腔疾病的敏感性，但疾病的确切原因尚不清楚。据报道，诱导转录因子NF-κB是许多炎症介质的关键调节剂，在腹腔患者的发炎粘膜中被激活，并进一步参与了各种肠道疾病中粘膜感染的进展。我们已经确定了一种新型的调节元件，即长的非编码RNA（LNCRNA）13（LNC13），该元件在培养细胞中调节NF-κB依赖性基因表达，并且重要的是，在腹腔患者活检中下调。该LNCRNA还包含与腹腔疾病和炎症性肠病（IBD）相关的单个核苷酸多态性（SNP），如全基因组关联研究（GWAS）所评估。我们认为，LNC13在维持肠内稳态中起着重要作用，并且LNC13表达或功能的失调可能影响肠中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，我们提出了3个具体目标。在AIM 1中，我们将进一步表征人类LNC13，并将产生腹腔患者的LNC13-相关基因组谱，以建立LNC13及其调节剂作为治疗干预的诊断或新靶标的新型生物标志物。在AIM 2中，我们将定义LNC13在炎症状态下如何差异调节，从而导致促炎性介质的表达增加。最后，在AIM 3中，我们将确定LNC13调节NF-κB依赖性炎症基因表达的机制，并检查LNC13对肠道炎性疾病模型中炎症进展的贡献。