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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：
10424970
负责人：
M Mahmood Hussain
金额：
$ 26.95万
依托单位：
NYU LONG ISLAND SCHOOL OF MEDICINE
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424970
关键词：
Effects miR 30c deficiency plasma

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.

高血浆胆固醇水平是动脉粥样硬化的主要危险因素，可以通过抑制脂蛋白来降低。产生；然而，这与脂肪变性有关。我们发现，miR-30c的过度表达降低了饮食- 诱导C57BL/6J野生型和apoE−/−小鼠高胆固醇血症和动脉粥样硬化。相反，抑制肝脏miR-30c可增加血浆胆固醇和动脉粥样硬化。基于这些令人兴奋的已发表的数据，我们假设内源性miR-30c是脂代谢的重要调节因子 MiR-30c缺乏会增加血浆和组织的脂质、血浆细胞因子和动脉粥样硬化。我们会使用双重敲除(DKO)Mir30c1−/−；Mir30c2−/−和Triple KO来评估这一假说 Mir30c1−/−；Mir30c2−/−；apoE−/−小鼠，饲喂含果糖和不含果糖的饲料和西式饲料。接下来，我们将建立 MiR-30c在高胆固醇血症及早、晚期发病中的直接和特异性作用不同基因敲除小鼠肝和脾中miR-30c重新表达的动脉粥样硬化病变战略。此外，使用类似的敲除和重新表达策略，我们将阐明生理学机制(肝脂蛋白产生、新生脂肪生成和巨噬细胞细胞因子产生) 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-30c缺陷解除MTP调控的分子假说，肝细胞中的LPGAT1和ELOVL5；巨噬细胞中的IKKα引起高胆固醇血症，脂肪变性，以及促炎细胞因子的产生。这些研究将确定内源性miR-30c的重要性。在调节血浆和组织脂质和细胞因子的产生方面，并将阐明生理学， MiR-30c调控多种生物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以及肝脏和巨噬细胞特异性miR-30c可对抗饮食诱导的代谢紊乱。