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：
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
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/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

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（由申请人提供）：乳糜泻是一种由摄入麸质的免疫反应引起的肠道炎症性疾病，这种反应会产生肠道炎症，随着时间的推移，会导致肠道内壁损伤和营养吸收不良。饮食中的麸质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 是导致乳糜泻的原因之一。是许多炎症介质的关键调节因子，在乳糜泻患者的发炎粘膜中被激活，而且肠道参与多种疾病中粘膜炎症的进展，我们已经确定了一种新的调节元件，即长非编码 RNA (lncRNA) 13 ( lnc13)，它调节培养细胞中 NF-κB 依赖性基因的表达，重要的是，在乳糜泻患者活检中下调。该 lncRNA 也含有单核苷酸。通过全基因组关联研究 (GWAS) 评估，多态性 (SNP) 与乳糜泻和炎症性肠病 (IBD) 相关。我们认为，lnc13 在维持肠道稳态以及 lnc13 表达失调中发挥着重要作用。功能可能影响肠道中 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，在目标 1 中，我们将进一步表征人类 lnc13，并生成乳糜泻患者的 lnc13 相关基因组图谱，以便将 lnc13 及其调节因子建立为诊断的新生物标志物或治疗干预的新靶标。目标 2，我们将定义 lnc13 在炎症状态下如何受到差异性调节，从而导致促炎介质表达增加。最后，在目标 3 中，我们将确定其机制。 lnc13 调节 NF-κB 依赖性炎症基因表达，并在肠道炎症疾病体内模型中检查 lnc13 对炎症进展的贡献。