RNA modification in cardiometabolic disease

项目总结 新陈代谢途径的扰动形成了一些对人类最具破坏性的威胁的中心， 包括心血管疾病、肥胖和NASH。适当地维持代谢平衡需要 精确和同步的基因调控控制。最近，发现数以千计的哺乳动物 RNA经历了强烈影响转录动力学的化学修饰，这扩大了我们对 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。多条证据表明，m6A在生物生物学中起着关键作用，包括 干细胞更新，然而，化学修饰对新陈代谢控制中的RNA的影响就不那么好了 明白了。这项建议的目的是确定rna的生理作用和机制。 新陈代谢方面的改变。利用我们的初步研究表明肝脏M6A的情况是 随着饮食的改变并强烈富含生脂RNA，我们假设动态RNA 修饰对于严格调节肝脂代谢是必不可少的。强化这一前提，我们的研究 表明肝脏特异性敲除m6A安装机械会导致脂肪生成增加和 肝脂成分。在目标1中，我们研究了m6A在肝脂代谢和脂肪肝中的作用。 以及探索基于RNA修饰的新陈代谢治疗策略的机会 疾病。在AIM2中，我们定义了m6A修饰如何影响脂肪生成，并破译了等级和 M6A修饰酶与典型代谢转录调节因子的协同关系。 我们提出的研究有望为新陈代谢相关的新机制提供基本的见解 控制和RNA修改可以影响健康和疾病状态的模型。总而言之，我们的 研究发现了一种新的脂类降解途径，在这一应用中，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验证假设。

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.