Understanding the Role of a Long Noncoding RNA in Celiac Disease

描述（由申请人提供）：乳糜泻是一种肠道炎症性疾病，由对麸质摄入的免疫反应引起。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。虽然不耐受饮食麸质和已知的遗传因素已牵连在腹腔疾病的易感性，疾病的确切原因是未知的。据报道，诱导型转录因子NF-κB是许多炎症介质的关键调节因子，其在乳糜泻患者的发炎粘膜中被激活，并且还参与各种肠道疾病中粘膜炎症的进展。我们已经确定了一种新的调控元件，长链非编码RNA（lncRNA）13（lnc 13），它调节培养细胞中NF-κ B依赖性基因的表达，重要的是，在乳糜泻患者活检中下调。这种lncRNA还包含与乳糜泻和炎症性肠病（IBD）相关的单核苷酸多态性（SNP），如全基因组关联研究（GWAS）所评估的。我们认为lnc 13在维持肠道内环境稳定中起重要作用，并且lnc 13表达或功能的失调可能影响NF-κB依赖的肠道炎症过程。为了更好地理解lnc 13在NF-κB调节中的作用及其对乳糜泻的影响， 我们提出三个具体目标。在目标1中，我们将进一步表征人类lnc 13，并将生成乳糜泻患者的lnc 13相关基因组谱，以建立lnc 13及其调节因子作为诊断的新生物标志物或治疗干预的新靶点。在目标2中，我们将定义lnc 13在炎症状态期间如何差异调节，导致促炎介质表达增加。最后，在目标3中，我们将确定lnc 13调节NF-κ B依赖性炎症基因表达的机制，以及在肠道炎症性疾病的体内模型中检查lnc 13对炎症进展的贡献。

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.