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

基本信息

批准号：
10551905
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
项目类别：
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/10551905
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 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 lipoprotein cholesterol mortality mouse model novel uptake

项目摘要

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.

项目摘要控制胆固醇稳态控制的改变会导致病理过程，包括动脉粥样硬化，是西方社会死亡率最常见的原因。流行病学研究已有确定了许多有助于动脉粥样硬化的环境和遗传因素。特别是高水平低密度脂蛋白胆固醇（LDL-C）和低密度脂蛋白胆固醇（HDL-C）的水平与心血管疾病（CVD）风险增加有关。除了蛋白质编码基因外，非 - 包括microRNA（miRNA）在内的编码RNA最近已显示在调节基因中起关键作用表达。 miRNA表达的改变与包括CVD在内的许多疾病有关。我们以前的工作证明了miRNA在调节HDL-C和LDL-C中的重要性。在特别是，我们小组的工作和其他人确定miR-33a/b和mir-148a是细胞的关键调节剂胆固醇外排和摄取，HDL生物发生和LDL清除率。这些研究强调了操纵miRNA以控制循环的HDL-C和LDL-C的治疗潜力，控制脂质和葡萄糖代谢方面的miRNA仍然知之甚少。深入研究miR-33a/b和miR-148a调节葡萄糖和miR-148a的分子机制脂质代谢，我们最近开发了许多独特的鼠标模型，可以使我们定义 miR-33和miR-148a在控制体内脂质代谢和动脉粥样硬化中的贡献。使用尖端技术，我们将确定miR-33a/b和miR-148a的监管网络调节体外和体内脂质代谢，并评估抗MIR-的潜在治疗价值 33A/B和Antimir-148A治疗用于治疗心脏代谢性疾病，包括动脉粥样硬化和代谢综合征。此外，我们将继续努力识别和表征新颖的非编码 RNA，包括调节脂质代谢和其他过程的长期非编码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表达受流量调节并介导LDL 在动脉op骨区域的浸润和保留，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，我们旨在表征此过程的方式受监管。