Control Sterol and Lipoprotein Homeostasis by miRNA

通过 miRNA 控制甾醇和脂蛋白稳态

• 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
• 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

 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医学疾病的基础，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 更好地了解全身脂质稳态对生理，病理和药理刺激的反应。在前一个周期中，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、胆固醇逆向转运和动脉粥样硬化形成的作用。目前的建议包括两大组研究：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并研究它们在肝脏代谢控制中的作用。在本提案的前半部分，我们将使用一种新的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限制，恢复了肝脏人类miR-33 a和miR-33 b、人类miR-33靶特异性和人类样脂蛋白谱。拟议的研究将提供有关miR-33在人类功能性肝脏中治疗性沉默的后果的关键数据。另一方面，我们提出的证据表明，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的mRNA）的变化。在这些变化中，我们重点关注miR-183/96/182簇靶点TCF 7 L2，并提供证据表明SREBP 2-miR-183/96/182-TCF 7 L2通路介导体内他汀类药物刺激的肝脏葡萄糖产生。最近描述的他汀类药物的致糖尿病作用增强了这种新的保守途径的翻译相关性。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将测试人肝脏miR-33 a和miR-33 b对肝脏脂质代谢、脂蛋白分泌和动脉粥样硬化形成的功能作用。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-33 b对饮食诱导的脂肪肝和肝脏胰岛素抵抗的贡献。目的2将确定miR-183/96/182对肝脏和全身葡萄糖稳态的功能作用，通过确定每个miR对肝脏葡萄糖产生的贡献，确定miR簇和TCF 7 L2调节肝脏生成的机制，并研究miR-183/96/182及其功能靶标的水平是否在血糖控制改变的小鼠模型中改变。这些研究的见解将填补目前在病理生理学肝脏代谢控制方面的知识空白，并可能发现新的药理学靶点来管理肝脏疾病，糖尿病和心血管风险。