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生产;但是，这与脂肪变性有关。我们表明，miR-30c的表达过度降低了饮食 C57BL/6J野生型和APOE - / - 小鼠诱导的高胆固醇血症和动脉粥样硬化。反过来，肝脏miR-30c的抑制增加了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是脂质代谢和 miR-30c缺乏将增强血浆和组织脂质，血浆细胞因子和动脉粥样硬化。我们将使用双基因敲除（DKO）mir30c1 - / - ; mir30c2 - / - 和三重KO评估这一假设 mir30c1 - / - ; mir30c2 - / - ; apoe - / - 小鼠喂食和不含果糖的西方饮食。接下来，我们将建立 miR-30c在高胆固醇血症以及早期和晚期的发展中的直接和特定作用通过使用不同策略。此外，使用类似的淘汰赛和重新表达策略，我们将阐明生理机理（肝脂蛋白产生，从头脂肪生成和巨噬细胞因子的产生）参与了高胆固醇血症，脂肪变性，炎症反应和动脉粥样硬化的调节 mir-30c。此外，我们将评估miR-30c缺乏会导致MTP的分子假设，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，和促炎性细胞因子的产生。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以及细胞因子的产生中，将阐明生理， miR-30c调节各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受保护作用以及针对饮食诱导的代谢性疾病的肝和巨噬细胞特异性miR-30c。