Non-coding RNA regulation of cholesterol homeostasis and atherosclerosis

非编码RNA对胆固醇稳态和动脉粥样硬化的调节

• 批准号: 10350668
• 负责人: KATHRYN J MOORE
• 金额: $ 101.7万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350668
• 关键词: Area; Atherosclerosis; Award; Biogenesis; Biological; Biology; Cardiovascular Diseases; Cause of Death; Cholesterol; Cholesterol Homeostasis; Code; DNA; Data; Gene Expression; Goals; High Density Lipoproteins; Human; Inflammatory; Length; Lipoproteins; Mammals; Metabolism; MicroRNAs; Molecular; National Heart, Lung, and Blood Institute; Pathway interactions; Primates; Proteins; RNA; Regulation; Research Personnel; Role; Signal Transduction; Time; Transcript; United States; Untranslated RNA; Work; atherogenesis; cardiovascular health; diagnostic strategy; flexibility; novel; prognostic; programs; therapeutic target

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.

总结 在人类中，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的这些已被功能性的特点。一个重大的挑战 生物学领域的研究重点是研究这些神秘的RNA如何调节基因表达和生物学特性。 途径，并将这些发现的结果纳入当前的范式。脂蛋白领域 代谢和动脉粥样硬化在这些努力中落后了。我们正试图将这一切 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，到 迄今为止，lncRNA的功能已被证明难以剖析，部分原因是lncRNA与microRNA不同， 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，研究的每一种lncRNA都提出了新的独特的挑战， 需要灵活地改变路线或追求新的方向，因为它们出现。因此，该项目是理想的 NHLBI杰出研究者奖计划的支持。如本申请中所述，我们有 最近发现的灵长类动物特异性lncRNA调节胆固醇流出，HDL生物合成和 炎症信号，我们正在进一步表征它们的功能。我们激动人心的发现说明了 在这一领域有巨大的发现潜力。值得注意的是，这些灵长类特异性lncRNA在哺乳动物中并不保守。 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 现在正在研究其他在人类心血管健康中起作用的新型lncRNA和微肽， 疾病，研究将导致更好地了解胆固醇稳态的分子调节 和动脉粥样硬化，以及识别新的预后/诊断方法和治疗方法， 目标的