巨噬细胞 AMPK、炎症和动脉粥样硬化-猫眼课题宝

巨噬细胞 AMPK、炎症和动脉粥样硬化

批准号：

8586350

负责人：

Bingzhong Xue

金额：

$36.26万

依托单位：

GEORGIA STATE UNIVERSITY

依托单位国家：

美国

项目类别：

财政年份：

2011

资助国家：

美国

项目状态：

已结题

起止时间：

2011-12-01 至 2016-11-30

来源：

https://reporter.nih.gov/project-details/8586350

关键词：

5&apos -AMP-activated protein kinase Acute Address Adipocytes Adipose tissue Antigen Presentation Apolipoprotein E Apoptosis Arterial Fatty Streak Atherogenic Diet Atherosclerosis Body Weight Cardiac Death Cells Cholesterol Cholesterol Homeostasis Chronic Coculture Techniques Development Diet Disease Dominant-Negative Mutation Endoplasmic Reticulum Euglycemic Clamping Event Exhibits Fatty acid glycerol esters Gene Expression Genes Glucose Glucose Clamp Goals Immune In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Insulin Insulin Resistance Kinetics Knock-out Knockout Mice Knowledge Lead Lesion Link Lipids Lipoproteins Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Metabolic Metabolic Diseases Metabolic Pathway Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathology Pathway interactions Phagocytosis Phenotype Plasma Prevention Reporting Role Saturated Fatty Acids Signal Pathway Signal Transduction Signaling Molecule Staging System Testing Therapeutic Tissues Toxic effect Transgenic Mice Up-Regulation cytokine endoplasmic reticulum stress fatty acid oxidation feeding glucose metabolism glucose tolerance glucose uptake improved in vivo insulin sensitivity insulin signaling insulin tolerance lipid metabolism macrophage migration mouse model novel nutrient metabolism oxidation oxidized low density lipoprotein particle prevent protective effect reverse cholesterol transport sensor

项目摘要

项目成果

Bingzhong Xue的其他基金

相似基金

相关文献

中文摘要

翻译

描述（由申请人提供）：AMP活化蛋白激酶（AMPK）是一种进化保守的细胞能量传感器，可调节脂质、胆固醇和葡萄糖代谢中的代谢途径。我们已经报道了巨噬细胞AMPK在体外对脂质诱导的炎症和胰岛素抵抗具有保护作用。此外，在ApoE-/-小鼠中，通过5-氨基咪唑-4-甲酰胺-1-2-4-呋喃核糖苷（AICAR）激活AMPK减轻了动脉粥样硬化负担。然而，AMPK的多效性功能使得很难确定巨噬细胞AMPK在炎症相关代谢紊乱（包括动脉粥样硬化和胰岛素抵抗）发病机制中的作用。在该提议中，将使用具有巨噬细胞特异性显性阴性或组成型活性11 AMPK过表达的转基因小鼠（分别为DN 11和CA 11）和巨噬细胞特异性11 MAPK敲除（MAKO）小鼠来研究巨噬细胞AMPK在这些代谢紊乱中的作用。我们发现，从CA 11小鼠巨噬细胞有显着降低脂质和胆固醇诱导的ER应激，炎症和凋亡，这是与上调基因参与脂肪酸氧化和胆固醇流出。我们推测巨噬细胞AMPK通过促进脂肪氧化和胆固醇流出来调节巨噬细胞脂质和胆固醇稳态，从而防止脂质和胆固醇诱导的ER应激、炎症和细胞凋亡。这可能有助于巨噬细胞AMPK对动脉粥样硬化和胰岛素抵抗的保护作用。具体目标1将使用来自CA 11、DN 11和MAKO小鼠的巨噬细胞确定巨噬细胞AMPK防止脂质和胆固醇诱导的ER应激、炎症和凋亡的机制。我们将确定：1）AMPK是否通过促进胆固醇流出和脂肪酸氧化来调节巨噬细胞脂质和胆固醇稳态，以及2）这些途径是否在介导AMPK抑制脂质和胆固醇诱导的ER应激、炎症和凋亡中是必需的。具体目标2将使用与低密度脂蛋白受体敲除小鼠杂交的CA 11、DN 11和MAKO小鼠来确定巨噬细胞AMPK对动脉粥样硬化的保护作用。我们将确定：1）血浆脂蛋白表型，2）来自巨噬细胞的体内反向胆固醇转运，3）动脉粥样硬化程度，4）动脉粥样硬化病变中的巨噬细胞数量、脂质含量、ER应激、炎症和凋亡，和5）在这些喂食致动脉粥样硬化饮食的小鼠中，早期和晚期动脉粥样硬化病变中的巨噬细胞积累、ER应激、炎症和凋亡发展的动力学。具体目标3将使用CA 11、DN 11和MAKO小鼠确定巨噬细胞AMPK对胰岛素抵抗的保护作用。将在这些高脂肪饮食的小鼠中测定胰岛素敏感性和脂肪组织巨噬细胞浸润、ER应激和炎症。完成这些研究将大大提高我们对巨噬细胞AMPK在预防炎症相关代谢紊乱（包括动脉粥样硬化和胰岛素抵抗）中作用的认识。

英文摘要

DESCRIPTION (provided by applicant): AMP-activated protein kinase (AMPK) is an evolutionally conserved cellular energy sensor that regulates metabolic pathways in lipid, cholesterol and glucose metabolism. We have reported that macrophage AMPK protects against lipid-induced inflammation and insulin resistance in vitro. In addition, activating AMPK by 5- aminoimidazole-4-carboxamide-1-2-4-ribofuranoside (AICAR) in ApoE-/- mice alleviates atherosclerosis burden. However, the pleiotropic functions of AMPK make it difficult to determine specifically the role of macrophage AMPK in the pathogenesis of inflammation-associated metabolic disorders, including atherosclerosis and insulin resistance. In this proposal, transgenic mice with macrophage-specific over- expression of dominant negative or constitutively active 11AMPK (DN11 and CA11, respectively), and macrophage-specific 11MAPK knockout (MAKO) mice will be used to study the role of macrophage AMPK in these metabolic disorders. We find that macrophages from CA11 mice have significantly lower lipid- and cholesterol-induced ER stress, inflammation and apoptosis, which is associated with up-regulation of genes involved in fatty acid oxidation and cholesterol efflux. We hypothesize that macrophage AMPK regulates macrophage lipid and cholesterol homeostasis by promoting fatty oxidation and cholesterol efflux, thereby preventing lipid- and cholesterol-induced ER stress, inflammation and apoptosis. This may contribute to macrophage AMPK's protective effects against atherosclerosis and insulin resistance. Specific aim 1 will determine mechanisms by which macrophage AMPK prevents lipid- and cholesterol-induced ER stress, inflammation and apoptosis using macrophages from CA11, DN11 and MAKO mice. We will determine: 1) whether AMPK regulates macrophage lipid and cholesterol homeostasis by promoting cholesterol efflux and fatty acid oxidation, and 2) whether these pathways are necessary in mediating AMPK's suppression of lipid- and cholesterol-induced ER stress, inflammation and apoptosis. Specific aim 2 will determine the protective effects of macrophage AMPK against atherosclerosis using CA11, DN11 and MAKO mice crossed with low density lipoprotein receptor knockout mice. We will determine: 1) plasma lipoprotein phenotype, 2) in vivo reverse cholesterol transport from macrophages, 3) atherosclerosis extent, 4) macrophage number, lipid content, ER stress, inflammation and apoptosis in atherosclerotic lesions, and 5) kinetics of macrophage accumulation, ER stress, inflammation and apoptosis development in early and late atherosclerotic lesions in these mice fed an atherogenic diet. Specific aim 3 will determine the protective effects of macrophage AMPK against insulin resistance using CA11, DN11 and MAKO mice. The insulin sensitivity and adipose tissue macrophage infiltration, ER stress and inflammation will be determined in these mice on a high fat diet. Completing these studies will greatly improve our knowledge on the role of macrophage AMPK in the protection against inflammation-associated metabolic disorders, including atherosclerosis and insulin resistance.

期刊论文(0)

专著(0)

科研奖励(0)

会议论文