Control of Sterol and Lipoprotein Homeostasis by miRNA

miRNA 对甾醇和脂蛋白稳态的控制

基本信息

批准号：
8254375
负责人：
Angel Baldan
金额：
$ 37.5万
依托单位：
SAINT LOUIS UNIVERSITY
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：
2011-05-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254375
关键词：
Accounting Address Adenoviruses Animals Anti-Inflammatory Agents Anti-inflammatory Antisense Oligonucleotides Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Back Bile Acids Bile fluid Biliary Biological Biology Bone Marrow Cells Cessation of life Cholestasis Cholesterol Cholesterol Homeostasis Cholic Acids Clinical Complex Data Development Diet Down-Regulation Dyslipidemias Excretory function Feces Genes Goals Hepatic Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins Homeostasis Human Intervention Intestines Intrahepatic Cholestasis Introns LDL Cholesterol Lipoproteins Label Laboratories Lead Link Lipoproteins Liver Low Density Lipoprotein Receptor Measures Metabolic Metabolism MicroRNAs Modeling Mus Myocardial Infarction Oligonucleotides Outcome Output Pathway interactions Patients Peripheral Peripheral arterial disease Phospholipids Physiological Plasma Property Proteome Publishing Regimen Reporting Risk Factors Role SRE-2 binding protein Serum Sterols Stroke Subfamily lentivirinae Testing Tissues atherogenesis atheroprotective base cardiovascular disorder risk cholesterol control dietary supplements feeding hypercholesterolemia improved in vivo mRNA Expression mRNA Precursor macrophage novel overexpression protein expression public health relevance research study response reverse cholesterol transport sterol homeostasis

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the primary cause of heart attack, stroke, and peripheral artery disease, which collectively account for >30% of all deaths in the US. Multiple studies recognized abnormal cholesterol homeostasis as a risk factor for the development of atherosclerosis. We and others have recently reported on miR-33, a conserved microRNA that is encoded within intron 16 of SREBP-2. The clinical importance of SREBP-2 is revealed in hypercholesterolemic patients treated with statins, which reduce LDL-cholesterol levels by increasing hepatic expression of SREBP-2 and its target the LDL-receptor. Our published and preliminary studies show that physiological targets of miR-33 include ABCA1, a transporter critical for HDL lipidation and reverse cholesterol transport, and ATP8B1, a phospholipid flippase linked to intrahepatic cholestasis. The broad goal of this proposal is to determine the role of miR-33 on cholesterol, bile and lipoprotein homeostasis. We hypothesize that miR-33 controls key aspects of sterol mobilization, bile excretion and HDL metabolism. Importantly, since statins are usually prescribed to hypercholesterolemic patients, and statins induce the expression of miR-33, we speculate that statin-treated patients will have elevated levels of miR-33 and persistent down regulation of ABCA1 and ATP8B1 by miR-33. To address these questions, we propose the following 3 specific aims: 1) Determine the role of miR-33 in hepatic sterol homeostasis in primary hepatocytes and in mice, by measuring the effect of over expression or silencing of miR-33 on lipoprotein secretion and bile excretion; 2) Test the hypothesis that altered macrophage miR-33 expression results in changes in reverse cholesterol transport and atherosclerotic lesion size, by performing experiments in vivo to determine the role of macrophage miR-33 expression on cholesterol -/- mobilization and progression of atherosclerotic lesions in Ldlr mice ; and 3) Test the hypothesis that systemic silencing of miR-33 is atheroprotective in vivo, by characterizing the composition and biological properties of HDL generated following systemic silencing of miR-33, and by evaluating whether anti-miR-33 oligonucleotides synergize with the atheroprotective effects of statins in ApoE*3Leiden W hCETP mice. There are still multiple aspects of cholesterol homeostasis, cholestasis and atherogenesis that remain obscure. Our data suggest that the cholesterol-miR-33 axis modulates key aspects of hepatocyte and macrophage biology. We anticipate that our studies will provide new clues into the complex regulatory networks that control intracellular cholesterol levels, bile excretion and circulating lipoproteins. If our hypothesis is true, miR-33 might be a target for novel therapies to manage dyslipidemias and/or cholestasis. ! PUBLIC HEALTH RELEVANCE: We propose to characterize miR-33, which defines a novel pathway that controls cholesterol, bile and lipoprotein homeostasis. We hypothesize that miR-33 modulates the expression of key genes involved in different aspects of sterol metabolism. The results of these studies might lead to novel, improved ways to manage patients with hypercholesterolemia and/or patients with cholestasis. !

描述（由申请人提供）：动脉粥样硬化是心脏病发作，中风和周围动脉疾病的主要原因，这些原因占美国所有死亡的30％。多项研究将异常的胆固醇稳态视为动脉粥样硬化发展的危险因素。我们和其他人最近报告了miR-33，这是一种保守的microRNA，该microRNA编码在SREBP-2的内含子16中。 SREBP-2的临床重要性在接受他汀类药物治疗的高胆固醇血症患者中揭示了，从而通过增加SREBP-2的肝表达及其靶向LDL受体，从而降低LDL-胆固醇水平。我们发表的初步研究表明，miR-33的生理靶标包括ABCA1，这是一种对HDL脂质化和反向胆固醇转运至关重要的转运蛋白，以及与肝内胆汁淤积有关的磷脂Flippase ATP8B1。该提案的广泛目标是确定miR-33在胆固醇，胆汁和脂蛋白稳态上的作用。我们假设miR-33控制固醇动员，胆汁排泄和HDL代谢的关键方面。重要的是，由于他汀类药物通常是向高胆固醇患者开具的，而他汀类药物会诱导miR-33的表达，因此我们推测，经他汀类药物治疗的患者的miR-33水平升高，并持续降低miR-33的ABCA1和ATP8B1的调节。为了解决这些问题，我们提出以下3个特定目的：1）确定miR-33在原发性肝细胞和小鼠中的肝固醇稳态中的作用，通过测量MiR-33对脂蛋白分泌和胆汁的分泌的过度表达或沉默的影响； 2）检验了改变巨噬细胞miR-33表达的假设会导致反向胆固醇转运和动脉粥样硬化病变大小的变化，通过在体内进行实验来确定巨噬细胞miR-33表达在胆固醇 - / - 动员和动脉粥样硬化菌群中动脉粥样硬化菌群中的作用。 and 3) Test the hypothesis that systemic silencing of miR-33 is atheroprotective in vivo, by characterizing the composition and biological properties of HDL generated following systemic silencing of miR-33, and by evaluating whether anti-miR-33 oligonucleotides synergize with the atheroprotective effects of statins in ApoE*3Leiden W hCETP mice.胆固醇稳态，胆汁淤积和动脉粥样硬化仍然存在多个方面。我们的数据表明，胆固醇-MIR-33轴调节肝细胞和巨噬细胞生物学的关键方面。我们预计我们的研究将为控制细胞内胆固醇水平，胆汁排泄和循环脂蛋白的复杂调节网络提供新的线索。如果我们的假设是正确的，那么miR-33可能是治疗血脂异常和/或胆汁淤积的新疗法的靶标。呢公共卫生相关性：我们建议对miR-33进行特征，该图表定义了一种控制胆固醇，胆汁和脂蛋白稳态的新型途径。我们假设miR-33调节了与固醇代谢不同方面有关的关键基因的表达。这些研究的结果可能会导致新的，改进的方法来管理高胆固醇血症和/或胆汁淤积患者的患者。呢