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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要项目摘要：高胆固醇血症是动脉粥样硬化的独立危险因素，动脉粥样硬化是最常见的疾病冠状动脉疾病（CAD）的原因。大量临床前和临床研究表明降低血浆低密度脂蛋白胆固醇（LDL-C）水平和/或增强高密度脂蛋白功能是有效的方法以降低 CAD 的发病率。肝脏在维持胆汁酸（BA）、甘油三酯（TG）和通过协调调节许多基因和信号通路来维持胆固醇稳态。激活转录因子 3 (ATF3) 是 ATF/cAMP 反应元件结合 (ATF/CREB) 家族的成员转录因子，并被证明可以抑制巨噬细胞的炎症反应。迄今为止，肝脏的作用 ATF3 在调节胆固醇或胆汁酸代谢方面的作用尚不清楚。我们的初步研究有表明肝脏 ATF3 可能通过协调血浆胆固醇摄取来调节血浆胆固醇水平经肝脏与BA代谢。因此，肝脏 ATF3 可能调节肝脏 ATF3 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方法来检验这一假设。我们的研究可能有助于确定肝脏 ATF3 作为胆固醇和胆汁酸代谢的新型调节剂动脉粥样硬化。