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

在环境诱导的肠道应激期间 IMP1 识别 N6-甲基腺苷 (m6A) 的功能结果

• 批准号: 10194496
• 负责人: Kathryn Elizabeth Hamilton
• 金额: $ 26.4万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194496
• 关键词: Address; Adult; Adverse effects; Affect; Binding Proteins; Biology; Body Weight decreased; Carboxymethylcellulose; Cell Line; Cells; Child; Clinical; Colitis; Colon; Crohn' s disease; Data; Diagnosis; Disease; Disease Progression; Disease susceptibility; Dose; Environment; Environmental Risk Factor; Epithelial; Epithelial Cells; Feces; Food; Food Additives; Foundations; Functional disorder; Future; Gene Expression Profile; Global Change; Goals; Health; Histologic; Human; IGF2 gene; Immunoprecipitation; Incidence; Individual; Inflammatory Bowel Diseases; Intervention; Intestines; Knock-out; Knockout Mice; Knowledge; Label; Length; Maps; Measures; Mediating; Messenger RNA; Metabolic; Modeling; Modification; Monitor; Mus; Nucleotides; Oral; Pathogenesis; Pathology; Patients; Physiologic pulse; Physiological; Predisposition; Prevention; Proteins; Public Health; RNA; RNA Binding; RNA Biochemistry; RNA-Binding Proteins; Reader; Recipe; Research Project Grants; Resolution; Role; Site; Small Intestines; Sodium Dextran Sulfate; Stress; Testing; Tissues; Ulcerative Colitis; Uracil; Work; base; biological adaptation to stress; crosslink; crosslinking and immunoprecipitation sequencing; effective intervention; environmental stressor; epitranscriptomics; functional outcomes; gastrointestinal; improved; indexing; intestinal epithelium; irradiation; mRNA Stability; maltodextrin; mouse model; novel; novel therapeutics; patient population; response; western diet

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.

项目摘要 RNA修饰正在成为人类健康和疾病的调节因子，然而， 在特定组织中的作用仍然是该领域的一个关键空白。新的证据表明，环境压力， 包括那些影响肠道健康的，可能会改变RNA修饰。广泛使用的食品添加剂 是一种这样的环境应激源，其可能对肠道具有先前未认识到的不利影响， 健康目前的建议旨在了解食品添加剂对IGF 2 mRNA功能的影响 结合蛋白1（IGF 2BP 1/IMP 1），一种新描述的N-甲基腺苷（m6 A）修饰的mRNA的“阅读器”。 我们发现IMP 1在小肠和结肠的上皮细胞中表达。新数据 表明IMP 1在炎症性肠病（IBD）患者中上调，并且是炎症性肠病（IBD）患者中最常见的疾病之一。 在该患者群体中，所有已知的RNA修饰蛋白的表达上调。这项探索性研究补助金将 测试新的假设，即食品添加剂改变IMP 1的表达和/或功能，作为一个读者， m6 A修饰的mRNA，这反过来又可以促进IBD的发病机制。Aim 1利用尖端RNA 通过生物化学来表征在原代小鼠类结肠中由食品添加剂诱导的m6 A应激反应。 目的2使用新的Imp 1敲除小鼠来评估在以下情况下该IBD相关m6 A阅读器的缺失： 食品添加剂和上皮损伤模型。这些研究将有助于对基本的 RNA修饰的生物学及其对肠道健康和疾病的贡献。未来的工作将测试 食品添加剂对IBD患者IMP 1介导效应的影响，作为新疗法的基础。