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-?B, 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-?B-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-?B dependent inflammatory processes in the intestine. To better understand the role of lnc13 in NF-?B 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-?B-dependent inflammatory gene expression, as well as examine the contribution of lnc13 to progression of inflammation in in vivo models of intestinal inflammatory disease.
Celiac disease is an intestinal inflammatory disorder caused by an immune reaction to the ingestion of gluten; which affects about 1% of the US population. Although In tolerance to dietary gluten and known genetic factors have been implicated in susceptibility to celiac disease; the exact causes of the disease are unknown. We aim to determine how a particular novel regulatory element; known as a long noncoding RNA (lncRNA); might regulate NF-?B-dependent inflammatory processes that play a role in the progression of celiac disease. Deciphering the mechanisms by which lncRNAs contribute to the promotion of inflammation through NF-?B could reveal previously unknown causes of celiac disease; identify new biomarkers for diagnosis; and ultimately help us develop better tools and therapeutics to treat celiac disease.
|Castellanos-Rubio, Ainara; Fernandez-Jimenez, Nora; Kratchmarov, Radomir et al. (2016) A long noncoding RNA associated with susceptibility to celiac disease. Science 352:91-5|