Functional outcomes of N6-methyladenosine (m6A) recognition by IMP1 during environment induced intestinal stress

项目总结

PROJECT SUMMARY RNA modifications are emerging as regulators of human health and disease, however, the mechanisms of action in specific tissues remain a critical gap in the field. New evidence suggests that environmental stressors, including those that impact intestinal health, may alter RNA modifications. Food additives in widespread use are one such environmental stressor that may have previously unrecognized adverse effects on intestinal health. The current proposal seeks to understand the effects of food additives on the function of IGF2 mRNA binding protein 1 (IGF2BP1/IMP1), a newly described “reader” of N-methyladenosine (m6A)-modified mRNAs. We identified that IMP1 is expressed in epithelial cells that line the small intestine and colon. New data demonstrate that IMP1 is upregulated in patients with inflammatory bowel disease (IBD) and is one of the top upregulated of all known RNA modifying proteins in this patient population. This exploratory research grant will test the novel hypothesis that food additives alter IMP1 expression and/or function as a reader of m6A-modified mRNAs, which in turn could promote IBD pathogenesis. Aim 1 utilizes cutting-edge RNA biochemistry to characterize the m6A stress response induced by food additives in primary mouse colonoids. Aim 2 uses novel ​Imp1 knockout mice to evaluate deletion of this IBD-relevant m6A reader in the context of food additives and epithelial damage models. These studies will contribute to a new understanding of the basic biology of RNA modifications and their contributions to intestinal health and disease. Future work will test consequences of food additives on IMP1-mediated effects in patients with IBD as a basis for new therapeutics.