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Effects of miR-30c deficiency on plasma cholesterol and atherosclerosis

miR-30c 缺陷对血浆胆固醇和动脉粥样硬化的影响

基本信息

批准号：
9900861
负责人：
M Mahmood Hussain
金额：
$ 11.45万
依托单位：
NYU WINTHROP HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2021-05-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900861
关键词：
Ablation Affect Anabolism Apolipoprotein E Arterial Fatty Streak Atherosclerosis Biochemical Biological Bone Marrow Bone Marrow Cell Transplantation Cardiovascular Diseases Cause of Death Cholesterol Complex Data Development Diet Disease Disease Progression Fatty Acids Female Fructose Genes Goals Hepatic Hepatocyte Homeostasis Hyperlipidemia Inflammatory Inflammatory Response Knock-out Knockout Mice Kupffer Cells Laboratories Lipids Lipoproteins Liposomes Liver Metabolic Diseases Molecular Mus Myelogenous Myeloid Cells Pathway interactions Peritoneal Phospholipids Physiological Plasma Plasma Enhancement Play Production Publishing Regulation Risk Factors Role Slice Spleen Subfamily lentivirinae Testing Therapeutic Agents Time Tissues Triglycerides Wild Type Mouse base cytokine drinking water fatty acid oxidation hypercholesterolemia lipid biosynthesis lipid metabolism macrophage male mouse model novel novel therapeutics western diet

项目摘要

High plasma cholesterol levels, a major risk factor for atherosclerosis, can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. We showed that over expression of miR-30c lowers diet- induced hypercholesterolemia and atherosclerosis in C57BL/6J wild type and Apoe−/− mice. Conversely, inhibition of hepatic miR-30c increased plasma cholesterol and atherosclerosis. Based on these exciting published data, we hypothesize that endogenous miR-30c is an important regulator of lipid metabolism and that miR-30c deficiency will enhance plasma and tissue lipids, plasma cytokines and atherosclerosis. We will evaluate this hypothesis using double knockout (DKO) Mir30c1−/−;Mir30c2−/− and triple KO Mir30c1−/−;Mir30c2−/−;Apoe−/− mice fed chow and western diets with and without fructose. Next, we will establish the direct and specific role of miR-30c in the development of hypercholesterolemia and early and advanced atherosclerotic lesions by re-expressing miR-30c in the liver and spleen of these knockout mice using different strategies. Further, using similar knockout and re-expression strategies, we will elucidate physiological mechanisms (hepatic lipoprotein production, de novo lipogenesis and macrophage cytokine production) involved in the regulation of hypercholesterolemia, steatosis, inflammatory response and atherosclerosis by miR-30c. Moreover, we will evaluate the molecular hypothesis that miR-30c deficiency deregulates MTP, LPGAT1 and ELOVL5 in hepatocytes; and IKKα in macrophages to cause hypercholesterolemia, steatosis, and pro-inflammatory cytokine production. These studies will establish the importance of endogenous miR-30c in the regulation of plasma and tissue lipids and cytokine production, and will elucidate physiological, biochemical and molecular mechanisms involved in the regulation of various biological pathways by miR-30c. At the end, these studies will furnish novel information concerning the protective role of whole body as well as liver- and macrophage-specific miR-30c against diet-induced metabolic disorders.

高血浆胆固醇水平，动脉粥样硬化的主要危险因素，可以通过抑制脂蛋白生产;然而，这与脂肪变性有关。我们发现miR-30 c的过度表达降低了饮食- 在C57 BL/6 J野生型和Apoe−/−小鼠中诱导高胆固醇血症和动脉粥样硬化。相反地，抑制肝脏miR-30 c增加血浆胆固醇和动脉粥样硬化。基于这些令人兴奋的根据已发表的数据，我们假设内源性miR-30 c是脂质代谢的重要调节因子， miR-30 c缺乏会增强血浆和组织脂质、血浆细胞因子和动脉粥样硬化。我们将使用双敲除（DKO）Mir 30 c1 −/−; Mir 30 c2 −/−和三重KO评估该假设 Mir 30 c1 −/−; Mir 30 c2 −/−;Apoe−/−小鼠喂食含和不含果糖的食物和西方饮食。接下来，我们将建立 miR-30 c在高胆固醇血症和早期和晚期高胆固醇血症的发展中的直接和特异性作用使用不同的方法，通过在这些基因敲除小鼠的肝脏和脾脏中重新表达miR-30 c来治疗动脉粥样硬化病变战略布局此外，使用类似的敲除和重新表达策略，我们将阐明生理学的机制（肝脂蛋白生成、从头脂肪生成和巨噬细胞细胞因子生成）参与调节高胆固醇血症、脂肪变性、炎症反应和动脉粥样硬化， miR-30c。此外，我们将评估miR-30 c缺陷失调MTP的分子假设，肝细胞中的LPGAT 1和IKK VL 5;以及巨噬细胞中的IKKα，导致高胆固醇血症、脂肪变性，和促炎细胞因子的产生。这些研究将确定内源性miR-30 c在在调节血浆和组织脂质和细胞因子的产生，并将阐明生理， miR-30 c参与调节各种生物学途径的生化和分子机制。最后，这些研究将提供有关全身保护作用的新信息，肝脏和巨噬细胞特异性miR-30 c对抗饮食诱导的代谢紊乱。