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

项目总结 RNA修饰正在成为人类健康和疾病的调节器，然而， 在特定组织中的作用仍然是该领域的一个关键空白。新证据表明，环境应激源， 包括那些影响肠道健康的因素，可能会改变RNA的修饰。广泛使用的食品添加剂 是一种这样的环境应激源，可能会对肠道产生以前未被认识到的不利影响 健康。目前的提案试图了解食品添加剂对IGF2基因功能的影响 结合蛋白1(IGF2BP1/IMP1)，一个新描述的N-甲基腺苷(M6A)修饰的mRNAs的“阅读器”。 我们发现IMP1在排列在小肠和结肠的上皮细胞中表达。新数据 证明IMP1在炎症性肠病(IBD)患者中表达上调，是最常见的 上调了该患者群体中所有已知的RNA修饰蛋白。这项探索性研究拨款将 检验食品添加剂改变IMP1表达和/或作为阅读器功能的新假设 M6A修饰的mRNAs，进而促进IBD的发病。AIM 1利用尖端RNA 生物化学，以表征食物添加剂在原代小鼠结肠中诱导的m6A应激反应。 Aim 2使用新的​Imp1基因敲除小鼠来评估这种与IBD相关的M6A阅读器在 食品添加剂和上皮损伤模型。这些研究将有助于重新理解基本的 RNA修饰的生物学及其对肠道健康和疾病的贡献。未来的工作将考验 作为新疗法基础的食品添加剂对IMP1介导的IBD患者效应的影响。

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.