Role of microRNAs in lipid metabolism and cardiovascular disease

microRNA在脂质代谢和心血管疾病中的作用

基本信息

批准号：
8432502
负责人：
Carlos Fernandez Hernando
金额：
$ 24.22万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-06 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432502
关键词：
ATP-Binding Cassette Transporters Antisense Oligonucleotides Apoptosis Area Atherosclerosis Attention Attenuated Binding Proteins Biochemical Pathway Biogenesis Cardiovascular Diseases Cardiovascular system Carnitine Carnitine O-Palmitoyltransferase Cell Line Cellular biology Cholesterol Cholesterol Homeostasis Coenzyme A Data Development Disease Enzyme Inhibition Enzymes Equilibrium Essential Fatty Acids Fatty Acids Functional RNA Gene Expression Generations Genes Genetic Goals Growth Hepatic Hepatocyte High Density Lipoproteins Homeostasis Homologous Gene Human Hypertriglyceridemia In Vitro Insulin Insulin Resistance Insulin Signaling Pathway Lipids Lipoproteins Liver Mediating Metabolic syndrome Metabolism MicroRNAs Molecular Molecular Biology Mus Oxidoreductase Pathologic Processes Physiological Processes Plasma Process Publishing Regulation Regulatory Element Role SRE-1 binding protein SRE-2 binding protein Sterols Therapeutic Work base fatty acid metabolism fatty acid oxidation gene repression human IRS2 protein in vivo insight insulin signaling lipid metabolism lipoprotein cholesterol macrophage novel therapeutic intervention overexpression phosphorothioate public health relevance research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Aberrant regulation of cholesterol and lipid homeostasis leads to metabolic syndrome and cardiovascular diseases. microRNAs (miRNA) are short non-coding RNAs that control gene expression predominantly through post-transcriptional repression. They are implicated in the control of multiple physiological and pathological processes. However the specific roles of miRNAs in regulating cholesterol and lipoprotein metabolism are just beginning to be explored. Our previous work has shown that hsa-miR- 33a/b and its mouse homologue mmu-miR-33 (herein after referred to as miR-33), intronic miRNAs located within the sterol-regulatory element-binding protein (SREBP) 2 and 1 genes, respectively, in humans; regulate cholesterol homeostasis in concert with the SREBP host gene. MiR-33 inhibits the expression of the ATP-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apoA1 and high-density lipoprotein (HDL) biogenesis. Conversely, silencing of miR-33 in vivo increased hepatic ABCA1 and plasma HDL. In addition, our recent preliminary data suggest that miR-33 also coordinates genes regulating fatty acid metabolism and insulin signaling. For example, miR-33 targets carnitine O- octaniltransferase (CROT), Carnitine palmitoyltransferase 1A (CPT1a) and hydroxyacyl-CoA- dehydrogenase (HADHB), key enzymes involved in the regulation of fatty acid oxidation, and insulin receptor substrate 2 (IRS2), which regulates insulin signaling. Thus, we hypothesize that inhibition of miR-33 may represent a therapeutic target for ameliorating cardiometabolic disease, including atherosclerosis and metabolic syndrome. The objective of this proposal is to determine the molecular mechanism underlying the miR-33-mediated responses in cardiometabolic disease. We propose the following specific Aims: Aim 1. To delineate the role of miR-33 in regulating cholesterol metabolism, - oxidation of fatty acid and insulin signaling in vivo and Aim 2. To define the role of miR-33 in lipid metabolism, insulin signaling, and atherosclerosis in vivo.

描述（由申请人提供）：胆固醇和脂质稳态的异常调节导致代谢综合征和心血管疾病。 microRNA（miRNA）是短的非编码RNA，主要通过转录后抑制控制基因表达。它们与控制多种生理和病理过程有关。然而，miRNA在调节胆固醇和脂蛋白代谢中的特定作用才刚刚开始探索。我们以前的工作表明，HSA-MIR-33A/B及其小鼠同源物mmu-miR-33（称为miR-33之后），分别位于固醇调节元素结合蛋白（SREBP）2和1基因内的内含子miRNA，分别在人类中；与SREBP宿主基因共同调节胆固醇稳态。 miR-33抑制了ATP结合盒（ABC）转运蛋白ABCA1的表达，从而抑制了胆固醇对APOA1和高密度脂蛋白（HDL）生物发生的表达。相反，MiR-33体内miR-33的沉默增加了肝ABCA1和血浆HDL。此外，我们最近的初步数据表明，miR-33还协调调节脂肪酸代谢和胰岛素信号传导的基因。例如，miR-33靶向肉碱o-八烷基转移酶（CROT），肉碱棕榈酰转移酶1A（CPT1A）和羟基酰基脱氢酶（HADHB），关键酶，脂肪酸氧化氧化，胰岛素受体的调节（INSUNTARE 2（IRS）consimul 2（irsuns in Inspration 2），涉及脂肪酸氧化剂2（IRS2）。因此，我们假设抑制miR-33可能代表了改善心脏代谢疾病（包括动脉粥样硬化和代谢综合征）的治疗靶标。该提案的目的是确定心脏代谢疾病中miR-33介导的反应的分子机制。我们提出以下具体目的：目的1。描述miR-33在调节胆固醇代谢中的作用， - 脂肪酸和体内胰岛素信号传导的氧化和目标2。定义miR-33在脂质代谢，胰岛素信号传导以及VIVO中的作用。