Identification of Novel Genes/Pathways That Regulate Atherogenesis

调节动脉粥样硬化形成的新基因/途径的鉴定

• 批准号: 10199006
• 负责人: Yanqiao Zhang
• 金额: $ 51.53万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199006
• 关键词: 7alpha hydroxylase; Ablation; Apolipoprotein E; Atherosclerosis; Bile Acids; Bile fluid; Binding; CYP7A1 gene; CYP8B1 gene; Cardiovascular Diseases; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Cholic Acids; Clinical Research; Coronary Arteriosclerosis; Cyclic AMP Response Element; Data; Development; Enzymes; Family; Fatty Acids; Fatty Liver; Gene Expression; Genes; Health; Hepatic; High Density Lipoproteins; High Fat Diet; Human; Incidence; Inflammatory Response; Intestines; LDL Cholesterol Lipoproteins; Lead; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Metabolic Diseases; Mixed Function Oxygenases; Mus; Pathogenesis; Pathologic; Pathway interactions; Plasma; Play; Regulation; Risk Factors; Role; Signal Pathway; Sterols; Testing; Triglycerides; activating transcription factor; activating transcription factor 3; atherogenesis; bile acid metabolism; cholesterol absorption; feeding; hypercholesterolemia; improved; loss of function; macrophage; member; novel; overexpression; preclinical study; prevent; reverse cholesterol transport; scavenger receptor; transcription factor; uptake; western diet

Project Summary Project Summary: Hypercholesterolemia is an independent risk factor for atherosclerosis, the most common cause for coronary artery disease (CAD). Numerous preclinical and clinical studies have demonstrated that lowering plasma LDL cholesterol (LDL-C) levels and/or enhancing HDL functionality are effective approaches to lower the incidence of CAD. The liver plays a central role in maintaining bile acid (BA), triglyceride (TG) and cholesterol homeostasis by coordinating regulation of a number of genes and signaling pathways. Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP response element-binding (ATF/CREB) family of transcription factors, and is shown to inhibit inflammatory response in macrophages. So far, the role of hepatic ATF3 in regulating cholesterol or bile acid metabolism is completely unknown. Our preliminary studies have shown that hepatic ATF3 regulates plasma cholesterol levels likely by coordinating plasma cholesterol uptake by the liver and BA metabolism. As a result, hepatic ATF3 may regulate the development or regression of atherosclerosis. In this project, we will use both gain- and loss-of-function approaches to test this hypothesis. Our studies may help identify hepatic ATF3 as a novel regulator of cholesterol and bile acid metabolism and atherosclerosis.

项目摘要 项目概述：高胆固醇血症是动脉粥样硬化的独立危险因素， 冠状动脉疾病（CAD）的病因。大量临床前和临床研究表明， 降低血浆LDL胆固醇（LDL-C）水平和/或增强HDL功能是有效的方法 降低冠心病的发病率。肝脏在维持胆汁酸（BA）、甘油三酯（TG）和甘油三酯（TG）中起着核心作用。 胆固醇稳态通过协调调节的基因和信号通路的数量。激活 转录因子3（ATF 3）是ATF/cAMP反应元件结合（ATF/CREB）家族的成员， 转录因子，并显示抑制巨噬细胞中的炎症反应。到目前为止，肝脏的作用 ATF 3在调节胆固醇或胆汁酸代谢中的作用是完全未知的。我们的初步研究表明 显示肝ATF 3可能通过协调血浆胆固醇摄取来调节血浆胆固醇水平， 通过肝脏和BA代谢。因此，肝ATF 3可能调节肝纤维化的发展或消退。 动脉粥样硬化在这个项目中，我们将使用功能获得和功能丧失的方法来测试这个假设。 我们的研究可能有助于确定肝ATF 3作为胆固醇和胆汁酸代谢的新型调节剂， 动脉粥样硬化