RNA modification in cardiometabolic disease

心脏代谢疾病中的RNA修饰

• 批准号: 10295370
• 负责人: Tamer Sallam
• 金额: $ 55.97万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295370
• 关键词: Adult; Affect; Animals; Architecture; Binding; Biological; Biological Assay; Biological Process; Biology; Cardiometabolic Disease; Cardiovascular Diseases; Cells; Chemicals; Cholesterol; Chromatin; Chronic; DNA-Binding Proteins; Data; Diet; Disease; Enzymes; Epigenetic Process; Exons; Fasting; Fatty Liver; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomic DNA; Genomics; Goals; Health; Hepatic; Histones; Homeostasis; Knock-out; Lipids; Liver; Liver diseases; Location; Maintenance; Mammalian Cell; Maps; Messenger RNA; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolism; Methylation; Methyltransferase; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Obesity; Pathway interactions; Pattern; Physiological; Play; Protein Family; Proteins; RNA; RNA metabolism; Reader; Regulation; Regulator Genes; Reporting; Resolution; Role; Series; Site; Stress; Testing; Therapeutic; Tissues; Transcript; Translations; Triglycerides; Untranslated Regions; Viral Vector; base; dietary; experimental study; gain of function; in vivo; insight; lipid biosynthesis; lipid metabolism; liver metabolism; mRNA Stability; methylome; mortality; nonalcoholic steatohepatitis; novel; promoter; response; ribosome profiling; stem cell division

PROJECT SUMMARY Perturbations in metabolic pathways form the epicenter of some of the most devasting threats to mankind, including cardiovascular disease, obesity and NASH. Proper maintenance of metabolic homeostasis requires precise and synchronized control of gene regulation. Recently, the discovery that thousands of mammalian RNAs undergo chemical modifications that powerfully impacts transcript dynamics expands our understanding of gene regulatory mechanisms. N6-methyladenosine methylation (m6A) is the most common internal RNA modification. Multiple lines of evidence suggest that m6A plays a critical role in organismal biology, including stem cell renewal, however, the impact of chemical modifications on RNA in metabolic control is less well understood. The objective of this proposal is to define the physiologic contribution and mechanisms of RNA modifications in metabolism. Capitalizing on our preliminary studies showing that the hepatic m6A landscape is altered in response to diet and strongly enriches lipogenic RNAs, we hypothesize that dynamic RNA modifications are essential for tight regulation of hepatic lipid metabolism. Reinforcing this premise, our studies show that liver-specific knockout of m6A installing machinery leads to increased lipogenesis and alterations in hepatic lipid composition. In aim1, we investigate the function of m6A in hepatic lipid metabolism and fatty liver disease as well as explore opportunities for RNA modification based therapeutic strategies in metabolic disease. In aim2, we define how m6A modifications impact lipogenesis and decipher the hierarchical and cooperative relationship between m6A modifying enzymes and canonical metabolic transcriptional modulators. Our proposed studies are expected to shed fundamental insight into novel mechanisms involved in metabolic control and a model by which RNA modifications can impact health and disease states. In summary, our studies identify a new pathway for lipid degradation and in this application, we propose a series of molecular, cell biological, and animal studies to extend our preliminary observations and test out hypothesis.

项目摘要 代谢途径中的扰动构成了一些对人类最破坏性威胁的中心， 包括心血管疾病，肥胖和纳什。适当维持代谢稳态需要 基因调控的精确和同步控制。最近，发现成千上万的哺乳动物的发现 RNA经历了有力影响笔录动态的化学修饰，扩大了我们的理解 基因调节机制。 N6-甲基拉第义甲基甲基化（M6A）是最常见的内部RNA 修改。多种证据表明，M6A在有机体生物学中起着至关重要的作用，包括 然而，干细胞更新，化学修饰对RNA在代谢控制中的影响不太好 理解。该建议的目的是定义RNA的生理贡献和机制 代谢的修饰。利用我们的初步研究表明肝M6A景观是 对饮食的响应改变并强烈丰富了脂肪生成RNA，我们假设该动态RNA 修饰对于严格调节肝脂质代谢至关重要。加强这一前提，我们的研究 证明M6A安装机械的特定肝脏敲除导致脂肪生成增加和改变 肝脂质成分。在AIM1中，我们研究了M6A在肝脂质代谢和脂肪肝中的功能 疾病以及探索代谢中基于RNA修饰的治疗策略的机会 疾病。在AIM2中，我们定义了M6A修改如何影响脂肪生成并破译层次结构和 M6A修饰酶与规范代谢转录调节剂之间的合作关系。 我们提出的研究预计将对参与代谢的新型机制进行基本洞察力 控制和RNA修饰会影响健康和疾病状态的模型。总而言之，我们的 研究确定了一种新的脂质降解途径，在此应用中，我们提出了一系列分子， 细胞生物学和动物研究，以扩展我们的初步观察并检验假设。