Licensing LncRNAs in Atherosclerosis

项目总结 全球1800万心血管死亡病例中的大部分被认为是由动脉粥样硬化引起的， 也许是影响人类的最具破坏性的病理过程。最近新陈代谢的激增 骚乱将确保动脉粥样硬化不会就这么消失。这个应用程序解决了大量 知识差距，并利用我们小组的最新发现和新的初步证据 提示长非编码RNA(LncRNAs)影响动脉粥样硬化的发生和发展 心脏代谢异常。这项提案的目标是1)定义lncRNA在 心脏代谢性疾病，2)提高我们对lncRNA之间复发关系的理解 保守和功能，以及3)测试基于lncRNA的心血管治疗策略的有效性 疾病。与此应用程序的目标保持一致，我们的多中心协作团队拥有以下方面的集体专业知识 LncRNA生物学、动脉粥样硬化和代谢性疾病、表观基因组图谱方法和解剖 人类疾病中的基因-表型关系。这一提议的首要假设是，有可能 是在脂类代谢中具有作用的InncRNAs，这些作用尚未被表征，并且当被上下文靶向时 特异性，它们可以减轻相关模型中的疾病表型。使用综合筛选平台 结合小鼠和人类的研究，我们发现了与肝脏脂质代谢有关的新的lncRNA，开发了一种 强大的管道，优先考虑lncRNA功能发现，并引入体内lncRNA的新工具 微扰。目的1，将确定巨噬细胞lncRNAs在动脉粥样硬化中的作用并探索机会 用于靶向病变的基于lncRNA的疗法。在目标2中，我们研究了lncRNAs在肝脏中的功能。 尽管序列进化，但脂类代谢和跨物种功能保守的证据的测试。 这些研究有望从根本上洞察非编码基因调控的重要性。 心脏代谢控制，并为心血管疾病的基于lncRNA的治疗提供了一个框架。在……里面 综上所述，这一面向发现的建议将填补动脉粥样硬化领域的实质性知识空白 和印第安纳核糖核酸生物学。

PROJECT SUMMARY The majority of the 18 million worldwide cardiovascular deaths are thought to be due to atherosclerosis, perhaps the single most devastating pathologic process affecting mankind. The recent surge in metabolic disturbances will ensure that atherosclerosis will not just fade away. This application addresses substantial knowledge gaps and capitalizes on recent discoveries from our group and new preliminary evidence suggesting that long noncoding RNAs (lncRNAs) influence the development of atherosclerosis and cardiometabolic abnormalities. The objective of this proposal is to 1) define the contributions of lncRNAs in cardiometabolic diseases, 2) improve our understanding of recurrent relationships between lncRNA conservation and function and 3) test the efficacy of lncRNA-based therapeutic strategies in cardiovascular disease. Aligned with goals of this application our multicenter collaborative group has collective expertise in lncRNA biology, atherosclerosis and metabolic disease, epigenomic profiling methodologies, and dissecting gene-phenotype relationships in human disease. The overarching hypothesis of this proposal is that there may be lncRNAs with roles in lipid metabolism that are yet to be characterized and when targeted with context specificity they can mitigate disease phenotypes in relevant models. Using an integrative screening platform combing mouse and human studies, we identify novel lncRNA involved in hepatic lipid metabolism, develop a robust pipeline that prioritizes lncRNA functional discovery, and introduce new tools for lncRNA in vivo perturbations. Aim 1, will determine role of macrophage lncRNAs in atherosclerosis and explore opportunities for lncRNA-based therapeutics targeting lesions. In Aim 2, we investigate the function of lncRNAs in hepatic lipid metabolism and test for evidence of cross-species functional conservation despite sequence evolution. These studies are expected to shed fundamental insight into the significance of noncoding gene regulation in cardiometabolic control and provide a framework for lncRNA-based therapeutics in cardiovascular disease. In summary, this discovery-oriented proposal will fill substantial knowledge gaps in the fields of atherosclerosis and lncRNA biology.