Dynamic RNA modifications that control gene expression in diabetes

控制糖尿病基因表达的动态 RNA 修饰

• 批准号: 10701667
• 负责人: Daniel James Wilinski
• 金额: $ 8.67万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10701667
• 关键词: 5' Untranslated Regions; Affect; Anatomy; Beta Cell; Biochemical; 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; Goals; 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; Production; Property; Proteins; RNA; RNA Splicing; RNA methylation; Regulation; Research; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Signal Transduction; Site; Somatomedins; Specific qualifier value; Speed; System; Testing; Training; Translations; Work; calcium indicator; diabetes mellitus therapy; diabetic; experimental study; fly; genetic manipulation; in vivo; insight; insulin regulation; insulin signaling; insulin-like peptide; knock-down; mRNA Translation; 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

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.

项目概要 遗传和环境因素在糖尿病的病因学中起着重要作用。这些因素如何相互作用 促进疾病仍不清楚。 N6-甲基腺苷 (m6A) 是一种动态 mRNA 修饰，可以指导 剪接命运和稳定性、促进 mRNA 翻译并整合营养信息。果蝇 胰岛素生成细胞 (IPC) 中 m6A 水平降低的黑腹果蝇、果蝇患有糖尿病；这个表型是 因摄入营养丰富的饮食而加剧。编码胰岛素系统中蛋白质的 mRNA 是 果蝇大脑中甲基化。这些结果表明 m6A 在胰岛素系统中发挥着关键作用。然而， m6A 促进糖尿病发展的机制尚不清楚。的力量 果蝇遗传学、IPC 的解剖、系统的相对简单性以及最新发展 直接 RNA 测序将用于揭示 m6A 控制基因的机制 IPC 中的表达。中心假设是 IPC 中 m6A 的减少会损害必要的动态 对胰岛素系统的翻译控制。目标 1 和 2 (K99) 将重点关注细胞内在机制 对 m6A 调节的丧失敏感。这些将揭示依赖于 m6A 的细胞生物学特性 适当的胰岛素输出。目标 2 和 4 (R00) 将探测细胞外在因素，这需要 m6A，整合 外部输入。这些将阐明 m6A 如何影响胰岛素受体翻译以及 m6A 水平如何 对营养状态做出反应。总之，这项拟议的工作将定义 mRNA m6A 甲基化在 IPC 的功能并揭示代谢输入如何调节 m6A 对 mRNA 的控制。这将推进我们的 了解 RNA 控制并可能有助于发现糖尿病预防的治疗靶点 和治疗。