Transcriptional control of microRNAs in lipid metabolism and atherosclerosis

microRNA在脂质代谢和动脉粥样硬化中的转录控制

• 批准号: 9106118
• 负责人: Thomas A Vallim
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9106118
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Affect; Animals; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attenuated; Cardiovascular Diseases; Cause of Death; Cholesterol; Data; Descending aorta; Diet; Disease; Disease Progression; Excretory function; Fatty acid glycerol esters; Foam Cells; Gene Targeting; Genes; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Inflammation; Kupffer Cells; Lesion; Lipids; Lipoproteins; Liver; Mediating; Metabolism; MicroRNAs; Modeling; Molecular; Mus; Nuclear Receptors; Pathogenesis; Pathway interactions; Plasma; Play; Property; RNA; Role; Site; Sterols; Structure of brachiocephalic artery; Testing; Therapeutic; Time; Transcriptional Regulation; Transport Process; United States; Untranslated RNA; aortic arch; atheroprotective; base; cholesterol transporters; cytokine; feeding; genetic signature; in vivo; lipid metabolism; lipoprotein cholesterol; macrophage; mouse model; novel; novel therapeutics; particle; public health relevance; receptor; reverse cholesterol transport; treatment strategy

 DESCRIPTION (provided by applicant): Cholesterol imbalance plays a central role in multiple diseases, particularly cardiovascular disease, and the leading cause of death in the United States. Lipid-loaded macrophage foam cells are a critical determining factor in the pathogenesis of atherosclerosis. MicroRNAs are small non-coding RNA molecules that regulate both cholesterol and lipoprotein metabolism, and may significantly contribute to disease progression. We identified miR-144 as a novel regulator of lipid metabolism that is also regulated by the nuclear receptor farnesoid X receptor (FXR). We identified the cholesterol transporter ABCA1 as a miR-144 target gene, and showed that increased hepatic expression of miR-144 decreased ABCA1 protein and plasma cholesterol levels. Consequently, we hypothesized that silencing miR-144 may have therapeutic potential because, first it would increase the levels of atheroprotective HDL particles; and secondly, it may enhance reverse cholesterol transport (RCT) due to increased ABCA1 levels in macrophages. In the current proposal we now demonstrate that silencing miR-144 is atheroprotective. In Specific Aim 1, we show preliminary data where silencing miR- 144 in Ldlr-/- mice is atheroprotective in a regression model by en face analysis. We will now characterize atherosclerotic lesions in multiple vessels in detail, and determine whether prolonged silencing of miR-144 further enhances regression of atherosclerosis. In Specific Aim 2, we show preliminary analysis where silencing miR-144 attenuates progression of atherosclerosis in Ldlr-/- mice. We will now carry out detailed analysis of the lesions, and determine whether silencing miR-144 is also protective in a different model of atherosclerosis disease. Finally, in Specific Aim 3, we will determine the molecular mechanism that underlies the atheroprotective effects of silencing miR-144. We will determine whether miR-144 silencing enhances RCT, alters HDL properties and affects global gene networks in both macrophages within lesions and liver. Thus, our proposal will determine the molecular basis for the atheroprotective effects of silencing miR-144, and establish this pathway as a bona-fide strategy to treat atherosclerosis.

 描述（由申请人提供）：胆固醇失衡在多种疾病中起着核心作用，特别是心血管疾病，并且是美国的主要死亡原因。载脂巨噬泡沫细胞是动脉粥样硬化发病机制中的关键决定因素。MicroRNA是小的非编码RNA分子，其调节胆固醇和脂蛋白代谢，并且可能显著促进疾病进展。我们鉴定了miR-144作为一种新的脂质代谢调节剂，它也受核受体法尼醇X受体（FXR）的调节。我们确定胆固醇转运蛋白ABCA 1为miR-144靶基因，并表明miR-144的肝脏表达增加会降低ABCA 1蛋白和血浆胆固醇水平。因此，我们假设沉默miR-144可能具有治疗潜力，因为首先它会增加动脉粥样硬化保护性HDL颗粒的水平;其次，由于巨噬细胞中ABCA 1水平增加，它可能会增强胆固醇逆向转运（RCT）。在目前的提议中，我们现在证明沉默miR-144具有动脉粥样硬化保护作用。在具体目标1中，我们通过正面分析显示了在回归模型中沉默Ldlr-/-小鼠中的miR- 144具有动脉粥样硬化保护作用的初步数据。我们现在将详细描述多支血管中的动脉粥样硬化病变，并确定miR-144的长期沉默是否进一步增强动脉粥样硬化的消退。在具体目标2中，我们显示了沉默miR-144减弱Ldlr-/-小鼠动脉粥样硬化进展的初步分析。我们现在将对病变进行详细分析，并确定沉默miR-144是否在不同的动脉粥样硬化疾病模型中也具有保护作用。最后，在具体目标3中，我们将确定沉默miR-144的动脉粥样硬化保护作用的分子机制。我们将确定miR-144沉默是否增强RCT，改变HDL特性并影响病变和肝脏内巨噬细胞的全局基因网络。因此，我们的建议将确定沉默miR-144的动脉粥样硬化保护作用的分子基础，并建立这种途径作为治疗动脉粥样硬化的真正策略。