Oxysterols, Atherosclerosis and Metabolic Syndrome

氧甾醇、动脉粥样硬化和代谢综合征

基本信息

批准号：
7622658
负责人：
DANIEL S ORY
金额：
$ 37.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7622658
关键词：
Affect Aneurysm Angiotensins Arterial Fatty Streak Atherosclerosis Biological Biological Markers Biology Biometry Blood Pressure Blood Vessels Body Weight decreased Calcium Cardiology Cardiovascular Diseases Cardiovascular system Caring Carotid Arteries Central obesity Cholesterol Clinical Trials Coronary heart disease Critical Pathways Data Detection Development Diabetes Mellitus Diet Disease Disease regression Doctor of Philosophy Dyslipidemias Endocrinologist Evaluation Exhibits Faculty Fatty acid glycerol esters Functional disorder Gelatinase B Genes Genetic Genetic Markers Genetic Polymorphism Genotype Glucose Glucose Intolerance Heart Valves Hepatic High Density Lipoproteins Homeostasis Human Hyperandrogenism Hyperglycemia Hyperinsulinism Hyperlipidemia Hypertension Hypertrophy Image Imaging Techniques Indium Individual Inflammatory Inflammatory Response Insulin Resistance Intervention Lesion Lipids Lipoproteins Measurement Measures Mechanics Mediating Mediator of activation protein Metabolic Metabolic syndrome Metabolism Minerals Modeling Molecular Morbidity - disease rate Mus NADP Necrosis Nuclear Receptors Numbers Obesity Pathologic Pathway interactions Patients Phenotype Plasma Play Polycystic Ovary Syndrome Production Protein Overexpression Regulation Reproducibility Research Research Personnel Resistance Risk Risk Factors Role Serum Side Site Smooth Muscle Myocytes Sterols Stimulus Structure Study models Supraoptic Vertical Ophthalmoplegia Testing Thick Time Tissues Transactivation Transcription Factor AP-1 Transgenic Mice Triglycerides Tunica Adventitia USF1 gene Ultrasonography Universities Up-Regulation Vascular Diseases Vascular calcification Vascular remodeling Washington Weight Gain Woman Work age related atherogenesis bench to bedside bone calcification cell motility clay coronary artery calcification cytokine cytotoxicity diabetic feeding genetic epidemiology genetic variant glucose metabolism intima media lipid metabolism loss of function macrophage medical schools member mortality multidisciplinary neutralizing antibody normal aging novel osteopontin oxidized lipid paracrine programs promoter radiologist response transcription factor USF translational study uptake vascular smooth muscle cell proliferation

项目摘要

Atheroclerosis is a major cause of morbidity and mortality in insulin-resistant states such as metabolic syndrome and obesity. Defective regulation of macrophage lipid metabolism plays a central role in the development of vascular lesions associated with these dyslipidemic states. During atherogenesis, macrophages respond to the challenge of lipid excess through enzymatic production of oxysterols and activation of feed-forward nuclear receptor pathways that induce transcriptional programs involved in lipid uptake and efflux, and negatively regulate inflammatory responses. In recent studies, we have shown that the products of the Niemann-Pick type C (NPC) disease genes, NPC1 and NPC2, are required for delivery of lipoprotein-derived cholesterol to sites of intracellular oxysterol synthesis. In this proposal, we will test the hypothesis that macrophage-derived oxysterols play a critical role in the regulation of lipid homeostasis in the vascular wall. We propose that impaired synthesis of side-chain oxygenated sterols will reduce cholesterol efflux and increase cholesterol accumulation in macrophages, and, in concert with increased levels of oxidized cholesterol, promote cytotoxicity and lesion formation. Production of specific macrophage-derived cholesterol metabolites additionally may play a critical role in governing plasma lipoprotein levels through regulation of hepatic lipoprotein synthesis and/or clearance of plasma lipoproteins. This hypothesis will be tested by the following specific aims: 1) To determine whether macrophage-specific NPC1 and NPC2 loss of function alters macrophage oxysterol synthesis, thereby disrupting lipid homeostasis and promoting atherosclerosis in a murine model, 2) To determine whether macrophage-derived cholesterol metabolites affect regulation of plasma lipoprotein levels in chimeric mice with macrophage-specific NPC1 and NPC2 loss of function, and 3) To assess the relationship between plasma oxysterol levels and coronary heart disease and determine if oxysterol levels change following weight loss in humans with the metabolic syndrome. These studies will contribute to our understanding of the role of macrophage-derived cholesterol metabolites in atherogenesis and regulation of lipoprotein metabolism. This project has the potential to transform the care of people with the metabolic syndrome by establishing these metabolites as novel biomarkers for detection of subclinical atherosclerotic disease.

动脉粥样硬化是胰岛素抵抗状态（例如代谢）发病率和死亡率的主要原因综合征和肥胖。巨噬细胞脂质代谢有缺陷在与这些血脂症状相关的血管病变的发展。在动脉粥样硬化期间，巨噬细胞通过酶促产生氧甲醇和激活前馈核受体途径，诱导参与脂质的转录程序吸收和排出，并对炎症反应负面调节。在最近的研究中，我们表明 Niemann-Pick型C（NPC）疾病基因，NPC1和NPC2的产物是递送所必需的脂蛋白衍生的胆固醇与细胞内氧蛋白酶合成部位。在此提案中，我们将测试假设巨噬细胞衍生的氧甲醇在调节脂质中起关键作用血管墙中的稳态。我们提出侧链氧化固醇的合成受损将减少胆固醇外排并增加巨噬细胞中的胆固醇积累，并与氧化胆固醇水平增加，促进细胞毒性和病变形成。特定的生产巨噬细胞衍生的胆固醇代谢产物还可能在治理血浆中起关键作用脂蛋白水平通过调节肝脂蛋白合成和/或血浆脂蛋白清除率。该假设将通过以下特定目的进行检验： 1）确定巨噬细胞特异性的NPC1和NPC2功能的损失是否改变了巨噬细胞甲醇合成，从而破坏脂质稳态并促进鼠模型中的动脉粥样硬化， 2）确定巨噬细胞衍生的胆固醇代谢物是否影响血浆脂蛋白的调节具有巨噬细胞特异性NPC1和NPC2功能丧失的嵌合小鼠的水平，并且 3）评估血浆氧蛋白酶水平与冠状动脉疾病之间的关系，并确定是否代谢综合征的人类体重减轻后，氧蛋白酶水平发生了变化。这些研究将有助于我们理解巨噬细胞衍生的胆固醇的作用脂蛋白代谢的动脉粥样硬化和调节中的代谢产物。这个项目有可能通过建立这些代谢物作为新颖的人来改变人们的护理检测亚临床动脉粥样硬化疾病的生物标志物。