Control Sterol and Lipoprotein Homeostasis by miRNA

通过 miRNA 控制甾醇和脂蛋白稳态

基本信息

批准号：
9106554
负责人：
Angel Baldan
金额：
$ 39.01万
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 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9106554
关键词：
Animal Model Animals Antisense Oligonucleotides Aorta Arterial Fatty Streak Basic Science Bile fluid Biochemical Bolus Infusion Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Cellular biology Cholesterol Cholesterol Homeostasis Clinical Data Dependovirus Diabetes Mellitus Diet Disease Fatty Liver Fibrosis Funding Gene Silencing Genes Gluconeogenesis Goals Hepatic Hepatocyte High Density Lipoproteins High Fat Diet High Prevalence Homeostasis Human Hyperglycemia Hyperinsulinism Hyperlipidemia Incidence Individual Inflammation Injection of therapeutic agent Insulin Insulin Resistance Intervention Introns Knowledge Label Laboratories Lead Link Lipids Lipoproteins Liver Liver diseases Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Mediator of activation protein Medical Messenger RNA Metabolic Control Metabolism MicroRNAs Modeling Molecular Mus Obese Mice Oligonucleotides Pathway interactions Patients Peripheral Pharmaceutical Preparations Physiological Plant Roots Plasma Population Preparation Public Health RNA-Induced Silencing Complex Role SRE-2 binding protein Safety Specificity Sterols Stimulus TCF7L2 gene Techniques Testing Therapeutic Time Tissues Up-Regulation Very low density lipoprotein atherogenesis base blood glucose regulation cardiovascular risk factor diabetes risk diabetogenic glucose production glycemic control human disease humanized mouse improved in vivo insight insulin sensitivity interest lipid metabolism mouse model novel overexpression pleiotropism public health relevance research study response reverse cholesterol transport

项目摘要

DESCRIPTION (provided by applicant): Deregulation of lipid metabolism is the basis of some of the most common medical disorders in western populations, such as cardiovascular disease, fatty liver diseases, hyperlipidemia, and diabetes. The long-term goal in our laboratory is to gain a better understanding of whole-body lipid homeostasis in response to physiological, pathological, and pharmacological stimuli. In the previous cycle, we studied the role of the statin-induced murine miR-33 on hepatic lipid metabolism, HDL and bile secretion, reverse cholesterol transport, and atherogenesis. The current proposal includes two large sets of studies: first, to continue our studies on miR-33; and second, to introduce additional statin-induced miRNAs and study their role on hepatic metabolic control. In the first half of this proposal, we will use a novel liver-humanized mouse to continue our currently funded studies on miR-33. These mice overcome the critical limitations of traditional murine models, restoring hepatic human miR-33a and miR-33b, human miR-33 target specificity, and human-like lipoprotein profiles. The proposed studies will provide critical data on the consequences of therapeutic silencing of miR-33 in a human, functional liver. On the other hand, we present evidence that statins induce changes in the murine hepatic RISCome (RNA-induced silencing complex-associated mRNAs) in vivo. Among these changes, we focus on the miR-183/96/182 cluster target TCF7L2, and present evidence that the SREBP2-miR-183/96/182-TCF7L2 pathway mediates statin-stimulated hepatic glucose production in vivo. The translational relevance of this new conserved pathway is enhanced by the recently described diabetogenic effect of statins. We will test these new ideas using a combination of biochemical, cell biology, and in vivo techniques. Specifically, Aim 1 will test the functional role of human hepatic miR-33a and miR-33b on hepatic lipid metabolism, lipoprotein secretion, and atherogenesis. Importantly, the unique liver-humanized mice will also allow us to test for the first time the contribution of miR-33b to diet-induced fatty liver and hepatic insulin resistance. Aim 2 will define the functiona role of miR-183/96/182 on hepatic and whole-body glucose homeostasis, by determining the contribution of each miR to hepatic glucose production, defining the mechanism by which the miR cluster and TCF7L2 regulate gluconeogenesis, and studying whether the levels of miR-183/96/182 and their functional targets are altered in murine models of altered glycemic control. The insights from these studies will fill a current gap of knowledge in pathophysiological hepatic metabolic control, and may uncover novel pharmacological targets to manage liver diseases, diabetes, and cardiovascular risk.

描述（由申请人提供）：脂质代谢失调是西方人群中一些最常见的医学疾病的基础，例如心血管疾病、脂肪肝疾病、高脂血症和糖尿病。我们实验室的长期目标是：获得更好地了解全身脂质稳态对生理、病理和药理刺激的反应在上一个周期中，我们研究了他汀类药物诱导的小鼠miR-33对肝脏脂质代谢、HDL和胆汁分泌、逆转胆固醇的作用。目前的提案包括两大组研究：第一，继续我们对 miR-33 的研究；第二，引入其他他汀类药物诱导的 miRNA 并研究它们对肝脏的作用。在本提案的前半部分，我们将使用新型肝脏人源化小鼠继续我们目前资助的 miR-33 研究，这些小鼠克服了传统小鼠模型的关键局限性，恢复了人类肝脏 miR-33a 和 miR。 -33b、人类 miR-33 靶标特异性和类人脂蛋白谱。另一方面，拟议的研究将为人类功能性肝脏中 miR-33 治疗沉默的后果提供关键数据。另一方面，我们提供了他汀类药物在体内诱导小鼠肝脏 RISCome（RNA 诱导的沉默复合物相关 mRNA）发生变化的证据，在这些变化中，我们重点关注 miR-183/96/182 簇靶标 TCF7L2，并提供了证据表明SREBP2-miR-183/96/182-TCF7L2 通路介导他汀类药物刺激的体内葡萄糖生成。最近描述的他汀类药物的糖尿病作用增强了新的保守途径，我们将结合生物化学、细胞生物学和体内技术来测试这些新想法，具体而言，目标 1 将测试人肝 miR-33a 和 miR-33a 的功能作用。 miR-33b 对肝脏脂质代谢、脂蛋白分泌和动脉粥样硬化形成的影响重要的是，独特的肝脏人源化小鼠也将使我们能够首次测试 miR-33b 对肝脏脂质代谢、脂蛋白分泌和动脉粥样硬化形成的影响。目标 2 将通过确定每个 miR 对肝脏葡萄糖生成的贡献（其机制）来确定 miR-183/96/182 对肝脏和全身葡萄糖稳态的功能作用。 miR 簇和 TCF7L2 调节糖异生，并研究 miR-183/96/182 的水平及其功能靶点在小鼠模型中是否发生改变这些研究的见解将填补目前病理生理学肝脏代谢控制方面的知识空白，并可能发现控制肝病、糖尿病和心血管风险的新药理学靶点。