Non-coding RNA regulation of cholesterol homeostasis and atherosclerosis

摘要 在人类中，带注释的长非编码RNA(LncRNA)的数量几乎是蛋白质的三倍 编码转录本，但只有不到50个这些转录本的功能特征。一项重大的挑战 生物学领域的目的是研究这些神秘的RNA如何调节基因表达和生物 研究方法，并将这些研究结果纳入现有范例。脂蛋白领域 新陈代谢和动脉粥样硬化在这些努力中已经落后。我们正试图弥合这一点 通过研究lncRNA在调节胆固醇代谢和动脉粥样硬化形成中的作用，形成了概念上的差距。至 迄今为止，lncRNAs的功能已被证明很难剖析，部分原因是与microRNAs不同，lncRNAs 缺乏统一的特征(除了长度)，它们可以形成多种类型的相互作用，包括RNA- RNA、RNA-DNA或RNA-蛋白质。因此，所研究的每一个lncRNA都提出了新的和独特的挑战 需要在出现新方向时灵活地改变路线或追求新方向。因此，该项目非常适合 由NHLBI的杰出调查员奖励计划支持。如本应用程序中所述，我们有 最近发现的灵长类特异的lncRNAs可以调节胆固醇的外流，高密度脂蛋白的生物发生和 炎症信号，我们正在进一步描述它们的功能。我们令人兴奋的发现说明了 在这一领域发现的巨大潜力。值得注意的是，这些灵长类特有的lncRNA在 其他哺乳动物，强调进一步研究人类lncRNA及其功能的重要性。我们是 现在正在寻找其他新的lncRNA和微肽，它们对人类心血管健康和 疾病，研究将导致更好地理解胆固醇稳态的分子调节 以及确定新的预后/诊断方法和治疗方法 目标。

SUMMARY In humans, the number of annotated long noncoding RNAs (lncRNA) is almost three times that of protein coding transcripts, yet fewer than 50 of these have been functionally characterized. A major challenge in all fields of biology is to investigate how these mysterious RNAs regulate gene expression and biological pathways, and to integrate the results of these findings into current paradigms. The field of lipoprotein metabolism and atherosclerosis has lagged behind in these efforts. We are attempting to bridge this conceptual gap by investigating the role of lncRNA in regulating cholesterol metabolism and atherogenesis. To date, the functions of lncRNAs have proven difficult to dissect, in part because unlike microRNAs, lncRNAs lack unifying features (other than length), and they can form numerous types of interactions, including RNA- RNA, RNA-DNA or RNA-protein. As such, each lncRNA studied presents new and unique challenges that require the flexibility to change course or pursue new directions as they arise. This project is thus ideal for support by the NHLBI's Outstanding Investigator Award Program. As described in this application, we have recently discovered primate-specific lncRNAs that regulate cholesterol efflux, HDL biogenesis and inflammatory signaling, and we are further characterizing their function. Our exciting findings illustrate the tremendous potential for discovery in this area. Notably, these primate-specific lncRNAs are not conserved in other mammals, highlighting the importance of further studies of human lncRNAs and their functions. We are now pursuing other novel lncRNAs and micropeptides that function in human cardiovascular health and disease, studies that will lead to better understanding of the molecular regulation of cholesterol homeostasis and atherosclerosis, as well as the identification of novel prognostic/diagnostic approaches and therapeutic targets.