RNA modification in cardiometabolic disease

项目摘要 代谢途径的紊乱是人类面临的一些最具破坏性的威胁的中心， 包括心血管疾病、肥胖和NASH。正确维持代谢平衡需要 基因调控的精确和同步控制。最近，研究人员发现， RNA经历化学修饰，有力地影响转录动力学，扩展了我们的理解 基因调控机制。N6-甲基腺苷甲基化（m6 A）是最常见的内部RNA 改性多种证据表明，m6 A在生物体生物学中起着关键作用，包括 然而，在干细胞更新中，化学修饰对RNA在代谢控制中的影响不太好 明白这项提案的目的是确定RNA的生理贡献和机制 代谢的改变。利用我们的初步研究表明，肝脏m6 A景观是 改变饮食和强烈丰富脂肪生成RNA，我们假设，动态RNA 修饰对于肝脏脂质代谢的严格调节是必需的。为了强化这一前提，我们的研究 表明肝脏特异性敲除m6 A安装机制导致脂肪生成增加和 肝脂质组成。在aim 1中，我们研究了m6 A在肝脏脂质代谢和脂肪肝中的作用 疾病以及探索基于RNA修饰的治疗策略的机会，在代谢 疾病在aim 2中，我们定义了m6 A修饰如何影响脂肪生成，并破译了脂肪生成的层次和结构。 m6 A修饰酶和典型代谢转录调节剂之间的合作关系。 我们提出的研究有望揭示参与代谢的新机制的基本见解。 控制和RNA修饰可以影响健康和疾病状态的模型。总之，我们的 研究确定了一种新的脂质降解途径，在该应用中，我们提出了一系列分子， 细胞生物学和动物研究来扩展我们的初步观察和测试假设。

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.