RNA modification in cardiometabolic disease

心脏代谢疾病中的RNA修饰

• 批准号: 10618327
• 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/10618327
• 关键词: Adult; Affect; Animals; Architecture; Binding; Biological; Biological Assay; Biological Process; Biology; Cardiometabolic Disease; Cardiovascular Diseases; Cells; Chemicals; Cholesterol; Chromatin; Chronic; DNA methylation profiling; DNA-Binding Proteins; Data; Diet; Disease; Enzymes; Epigenetic Process; Exons; Fasting; Fatty Liver; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomic DNA; Goals; Health; Hepatic; Histones; Homeostasis; Knock-out; Lipids; Liver; 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; RNA methylation; Reader; Regulation; Regulator Genes; Reporting; Resolution; Role; Series; Site; Stress; Testing; Therapeutic; Tissues; Transcript; Translations; Triglycerides; Untranslated Regions; Viral Vector; dietary; experimental study; fatty liver disease; gain of function; genomic locus; in vivo; insight; lipid biosynthesis; lipid metabolism; liver metabolism; mRNA Stability; methylome; mortality; nonalcoholic steatohepatitis; novel; posttranscriptional; 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.

项目概要 代谢途径的扰动构成了对人类一些最具破坏性的威胁的中心， 包括心血管疾病、肥胖和NASH。适当维持代谢稳态需要 基因调控的精确同步控制。最近，人们发现数以千计的哺乳动物 RNA 经历化学修饰，强烈影响转录动力学，拓展了我们的理解 基因调控机制。 N6-甲基腺苷甲基化 (m6A) 是最常见的内部 RNA 修改。多种证据表明 m6A 在生物体生物学中发挥着关键作用，包括 然而，干细胞更新中化学修饰对代谢控制中RNA的影响还不太清楚 明白了。该提案的目的是定义 RNA 的生理贡献和机制 新陈代谢的改变。利用我们的初步研究表明肝脏 m6A 景观是 因饮食而改变并强烈富集脂肪生成 RNA，我们假设动态 RNA 修饰对于严格调节肝脏脂质代谢至关重要。为了强化这个前提，我们的研究 表明肝脏特异性敲除 m6A 安装机制会导致脂肪生成增加和 肝脂质成分。在目标1中，我们研究了m6A在肝脏脂质代谢和脂肪肝中的功能 疾病以及探索基于 RNA 修饰的代谢治疗策略的机会 疾病。在 Target2 中，我们定义了 m6A 修饰如何影响脂肪生成并破译了分层和 m6A 修饰酶和典型代谢转录调节剂之间的合作关系。 我们提出的研究预计将为代谢相关的新机制提供基本见解 控制和 RNA 修饰影响健康和疾病状态的模型。综上所述，我们的 研究确定了脂质降解的新途径，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。