Novel insights into the molecular and cellular mechanism regulating lipid metabolism and atherosclerosis

对调节脂质代谢和动脉粥样硬化的分子和细胞机制的新见解

• 批准号: 10331792
• 负责人: Carlos Fernandez Hernando
• 金额: $ 85.01万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331792
• 关键词: Animal Model; Area; Arteries; Atherosclerosis; Biogenesis; Cardiometabolic Disease; Cardiovascular Diseases; Caveolae; Cells; Cholesterol; Cholesterol Homeostasis; Code; Data; Development; Disease; Electron Microscopy; Event; Gene Expression; Genes; Genetic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; In Vitro; Infiltration; Inflammation; Inflammatory; LDL Cholesterol Lipoproteins; Lead; Lipids; Lipoproteins; Low-Density Lipoproteins; Mediating; Metabolic syndrome; MicroRNAs; Molecular; Morbidity - disease rate; Pathologic Processes; Plasma; Play; Process; Proteins; Societies; Techniques; Therapeutic; Untranslated RNA; Work; atherogenesis; cardiovascular disorder risk; caveolin 1; cholesterol control; combat; defined contribution; epidemiology study; glucose metabolism; in vivo; innovation; insight; lipid metabolism; mortality; mouse model; novel; uptake

PROJECT SUMMARY Alterations in the control of cholesterol homeostasis can lead to pathological processes, including atherosclerosis, the most common cause of mortality in Western societies. Epidemiological studies have identified many environmental and genetic factors that contribute to atherogenesis. In particular, high levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased cardiovascular disease (CVD) risk. In addition to protein coding genes, non- coding RNAs including microRNAs (miRNAs) have recently shown to play a key role in regulating gene expression. Alteration in miRNAs expression has been associated to numerous diseases including CVD. Our previous work has demonstrated the importance of miRNAs in regulating HDL-C and LDL-C. In particular, work from our group and others identified miR-33a/b and miR-148a as key regulators of cellular cholesterol efflux and uptake, HDL biogenesis and LDL clearance. While these studies highlight the therapeutic potential of manipulating miRNAs to control circulating HDL-C and LDL-C, the effect of both miRNAs in controlling lipid and glucose metabolism remains poorly understood. To investigate in depth the molecular mechanism by which miR-33a/b and miR-148a regulate glucose and lipid metabolism, we have recently developed a number of unique mouse models that will allow us to define the contribution of miR-33 and miR-148a in controlling lipid metabolism and atherogenesis in vivo. Using cutting-edge techniques, we will identify the regulatory network through which miR-33a/b and miR-148a regulate lipid metabolism both in vitro and in vivo, and assess the potential therapeutic value of anti-miR- 33a/b and antimiR-148a therapy for treating cardiometabolic diseases including atherosclerosis and metabolic syndrome. Additionally, we will continue our efforts to identify and characterize novel non-coding RNAs, including long non-coding RNAs (lncRNAs) that regulate lipid metabolism and other processes that influence the development of CVD. In another different topic, we will also study the molecular mechanisms that regulate the initial steps of atherogenesis. We hypothesize that Cav-1/caveolae expression is regulated by flow and mediates LDL infiltration and retention in atheroprone areas leading to the progression of atherosclerosis. Using unique animal models and innovative electron microscopy technics we aim to characterize how this process is regulated.

项目摘要 胆固醇稳态控制的改变可导致病理过程，包括 动脉粥样硬化是西方社会最常见的死亡原因。流行病学研究 确定了许多环境和遗传因素，有助于动脉粥样硬化形成。特别是高水平 低密度脂蛋白胆固醇（LDL-C）和低水平的高密度脂蛋白胆固醇（HDL-C） 与心血管疾病（CVD）风险增加有关。除了蛋白质编码基因外， 近年来发现，包括microRNA（miRNAs）在内的编码RNA在调控基因表达中起着关键作用， 表情miRNA表达的改变与包括CVD在内的许多疾病相关。 我们以前的工作已经证明了miRNA在调节HDL-C和LDL-C中的重要性。在 特别是，我们小组和其他人的工作将miR-33 a/B和miR-148 a确定为细胞凋亡的关键调节因子。 胆固醇流出和摄取、HDL生物合成和LDL清除。虽然这些研究强调， 操纵miRNA控制循环HDL-C和LDL-C的治疗潜力， miRNA在控制脂质和葡萄糖代谢中的作用仍然知之甚少。 为了深入研究miR-33 a/B和miR-148 a调节葡萄糖的分子机制， 脂质代谢，我们最近开发了一些独特的小鼠模型，使我们能够定义 miR-33和miR-148 a在体内控制脂质代谢和动脉粥样硬化形成中的作用。使用 我们将通过尖端技术确定miR-33 a/B和miR-148 a的调控网络， 在体外和体内调节脂质代谢，并评估抗-miR-16的潜在治疗价值。 33 a/B和antimiR-148 a治疗包括动脉粥样硬化的心脏代谢疾病， 代谢综合征此外，我们将继续努力，以确定和表征新的非编码 RNA，包括调节脂质代谢和其他过程的长链非编码RNA（lncRNA）， 影响CVD的发展。 在另一个不同的主题中，我们还将研究调节蛋白质合成的初始步骤的分子机制。 动脉粥样硬化我们假设Cav-1/caveolae表达受血流调节，并介导LDL 在动脉粥样硬化区域的浸润和滞留导致动脉粥样硬化的进展。使用唯一 动物模型和创新的电子显微镜技术，我们的目标是表征这一过程是如何 监管.