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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要然而在特定组织中的作用仍然是该领域的关键差距。新证据表明，环境压力源，包括影响肠道健康的患者可能会改变RNA修饰。宽度使用的食品添加剂是一种这样的环境压力源，以前可能对肠道产生不认识的不良影响健康。当前的建议旨在了解食品添加剂对IGF2 mRNA功能的影响结合蛋白1（IGF2BP1/IMP1）是N-甲基丹代氨酸（M6A）修饰的MRNA的新描述的“读取器”。我们确定IMP1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）的患者中已更新，并且是最重要的该患者人群中所有已知的RNA修饰蛋白质的上调。这项探索性研究赠款将测试食物添加剂改变IMP1表达和/或功能作为读者的新假设 M6A修饰的mRNA，进而可以促进IBD发病机理。 AIM 1利用尖端的RNA 生物化学表征了原代小鼠结肠造成的食物添加剂引起的M6A应激反应。 AIM 2使用新颖的IMP1敲除小鼠来评估此与IBD相关的M6A读取器的缺失食品添加剂和上皮损害模型。这些研究将有助于对基本的新理解 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IMP1介导的IBD患者的影响的后果作为新疗法的基础。