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Dynamic RNA modifications that control gene expression in diabetes

控制糖尿病基因表达的动态 RNA 修饰

基本信息

批准号：
10370792
负责人：
Daniel James Wilinski
金额：
$ 8.82万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370792
关键词：
5&apos Untranslated Regions Affect Anatomy Beta Cell Biochemical Genetics Biological Biological Assay Biosensor Brain Calcium Cell physiology Cells Data Development Diabetes Mellitus Diabetes prevention Diet Disease Drosophila genus Drosophila melanogaster Endocrinology Environmental Risk Factor Etiology Exposure to Functional Imaging Gene Expression Genetic Genetic Translation Goals Head Human Immunofluorescence Immunologic Impairment In Vitro Insulin Insulin Receptor Mammals Measures Mentors Messenger RNA Metabolic Metabolic Diseases Methylation Methyltransferase Microscopy Modification Monitor Mutagenesis Non-Insulin-Dependent Diabetes Mellitus Nutrient Nutritional Output Pathway interactions Phenotype Play Positioning Attribute Pre-Clinical Model Prevention Prevention therapy Production Property Proteins RNA RNA Splicing RNA methylation Regulation Research Role S-Adenosylmethionine Signal Transduction Site Somatomedins Specific qualifier value Speed System Testing Training Translations Work calcium indicator diabetic experimental study fly genetic manipulation in vivo insight insulin regulation insulin signaling insulin-like peptide knock-down methylome molecular targeted therapies mouse model mutant new therapeutic target protein function receptor ribosome profiling role model stoichiometry sugar therapeutic target tool transcriptome sequencing translation assay

项目摘要

Project Summary Genetic and environmental factors play important roles in the etiology of diabetes. How these factors interact to promote disease remains unclear. N6-methyladenosine (m6A) is a dynamic mRNA modification that can direct splicing fate and stabilization, promote translation of mRNAs, and integrate nutritional information. Drosophila melanogaster, flies, with lowered levels of m6A in insulin-producing cells (IPCs) are diabetic; this phenotype is exacerbated by exposure to a nutrient-rich diet. mRNAs that encode proteins in the insulin system are methylated in the brain of flies. These results suggest that m6A plays a critical role in the insulin system. Yet, the mechanisms through which m6A contributes to the development of diabetes are unknown. The power of Drosophila genetics, the anatomy of the IPCs, the relative simplicity of the system, and the recent development of direct RNA-sequencing will be leveraged to uncover mechanisms through which m6A controls gene expression in IPCs. The central hypothesis is that reduced m6A in IPCs impairs necessary dynamic translational control over the insulin system. Aims 1 and 2 (K99) will focus on cell-intrinsic mechanisms that are sensitive to the loss of m6A regulation. These will uncover cell biological properties that depend on m6A for proper insulin output. Aims 2 and 4 (R00) will probe cell-extrinsic factors, which require m6A, that integrate external inputs. These will elucidate how m6A impacts insulin receptor translation and how the levels of m6A respond to nutritional state. Together, this proposed work will define a role for m6A methylation of mRNA in the function of IPCs and reveal how metabolic inputs modulate m6A control over mRNAs. This will advance our understanding of RNA control and may facilitate the discovery of therapeutic targets for diabetes prevention and therapy.

项目总结