HDL Dysfunction and Vascular Inflammation

HDL 功能障碍和血管炎症

基本信息

批准号：
7216745
负责人：
Kirkwood Arthur Pritchard
金额：
$ 36.78万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7216745
关键词：
3-nitrotyrosine Acids Acute-Phase Proteins African American Allopurinol Amino Acids Antibodies Aorta Apolipoproteins Apolipoproteins A Appendix Arteries Automobile Driving Binding Biochemistry Biological Assay Blood Vessels Bone Marrow Transplantation Cell physiology Chronic Chronic lung disease Class Clinical Consumption Crime Data Data Analyses Defect Disease Drug Design End Point Endothelial Cells Endothelium Enzymes Equilibrium Erythrocytes Functional disorder Gene Mutation Generations Genetic Genetically Engineered Mouse Globin Glutamic Acid Goals Hematopoietic Stem Cell Transplantation Hemoglobin Hereditary Disease High Density Lipoproteins Histology Hyperlipidemia Incubated Infarction Infiltration Inflammation Inflammatory Injury Ischemia Kidney Kidney Failure Knockout Mice Laboratories Lead Lipids Liquid substance Liver Longevity Low Density Lipoprotein Receptor Low Density Lipoprotein oxidation Low-Density Lipoproteins Lung Mediating Mediator of activation protein Modality Modeling Molecular Biology Mononuclear Morbidity - disease rate Mus Mutation Nitric Oxide Organ Outcome Oxidative Stress Pain Paper Pathology Patients Peptides Pharmaceutical Preparations Plasma Play Property Proteomics Reporting Research Personnel Role Sickle Cell Sickle Cell Anemia Solubility Stream Stroke Superoxides System Testing Tissues Transfusion Transgenic Mice Transgenic Organisms Triad Acrylic Resin Valine Vascular Diseases Vascular Endothelium Vasodilation Xanthine Oxidase aryldialkylphosphatase atheroprotective base concept cytokine design enzyme activity experience hypercholesterolemia improved inhaled nitric oxide inhibitor/antagonist macrophage mimetics mortality novel therapeutics prevent protective effect protein protein interaction sickling therapeutic target treatment effect vascular inflammation xanthine oxidase inhibitor

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this application is to determine the mechanisms by which vascular inflammation impairs vasodilation. Recent reports from this laboratory demonstrate that an apoA-l mimetic, 4F, dramatically improves endothelium-and eNOS-dependent vasodilation in two distinct murine models of vascular disease-hypercholesterolemia and sickle cell disease (SCD). On the basis that apoA-l mimetics were designed to improve HDL function, we hypothesize that oxidative stress and inflammation induce HDL dysfunction, which in turn impairs vasodilation. In this application, we will test this hypothesis in a disease state and a murine model whose vascular dysfunction is more closely associated with inflammation than hyperlipidemia, sickle cell disease (SCD). Although SCD is primarily a genetic disease, many consider the chronic state of inflammation to play a role in the mechanisms by which SCD impairs vasodilation. This application investigates the concept that inflammation plays a central role in impairing vascular dysfunction by determining how the sickling red cell raises up new "partner in crime" to induce vascular disease. The objectives of this application are to determine the interactions between inflammation, HDL function and proinflammatory lipids in hopes of identifying other down-stream "partner(s)" who team up with the sickling red cell to impair vasodilation. We will investigate the role of acute phase proteins, proinflammatory HDL, proinflammatory lipids and xanthine oxidase on vascular function in transgenic SCD mice. Bioassays of plasma from severe and non-severe SCD patients and control subjects will be used to identify and rank potential partners that impair vasodilation and shift the balance of nitric oxide (-NO) and superoxide anion (O2.-) generation in the vessel wall. Mechanisms will be investigated at the vascular level to determine how SCD induces endothelial cell dysfunction. Hematopoietic stem cell transplantation (HSCT) of SCD into genetically engineered mice will be used to test alternative hypotheses that low-density lipoprotein contributes to impaired vasodilation in SCD. HSCT of SCD into an apoA-l knockout mouse that expresses apoA-l-deficient HDL will be used to test the alternative hypothesis that D-4F does not improve HDL function to restore vasodilation. The utility of D-4F in improving outcomes will be tested at the level of survival, mechanisms of ischemic injury, organ pathobiology and proteomics of HDL interactions with other inflammatory mediators. On the basis that D-4F improves vasodilation in other systems, our data suggest that targeting HDL may be an effective means of protecting vascular function in diseases characterized by chronic states of inflammation. Through these studies, new treatment modalities may be realized for preventing vascular dysfunction in a variety of diseases characterized by increases in oxidative stress and inflammation.

描述（由申请人提供）：本申请的总体目标是确定血管炎症损害血管舒张的机制。该实验室最近的报告表明，apoA-l 模拟物 4F 在两种不同的血管疾病小鼠模型（高胆固醇血症和镰状细胞病 (SCD)）中显着改善内皮和 eNOS 依赖性血管舒张。基于 apoA-l 模拟物旨在改善 HDL 功能，我们假设氧化应激和炎症会诱导 HDL 功能障碍，进而损害血管舒张。在本申请中，我们将在疾病状态和小鼠模型中测试这一假设，与高脂血症、镰状细胞病 (SCD) 相比，小鼠模型的血管功能障碍与炎症的关系更为密切。尽管 SCD 主要是一种遗传性疾病，但许多人认为慢性炎症状态在 SCD 损害血管舒张的机制中发挥着重要作用。该应用通过确定镰状红细胞如何产生新的“犯罪伙伴”来诱发血管疾病，研究了炎症在损害血管功能障碍中发挥核心作用的概念。该应用的目的是确定炎症、高密度脂蛋白功能和促炎脂质之间的相互作用，希望找到与镰状红细胞合作损害血管舒张的其他下游“伙伴”。我们将研究急性期蛋白、促炎性高密度脂蛋白、促炎性脂质和黄嘌呤氧化酶对转基因 SCD 小鼠血管功能的作用。对严重和非严重 SCD 患者以及对照受试者的血浆进行生物测定，将用于识别和排名潜在的伙伴，这些伙伴会损害血管舒张并改变血管壁中一氧化氮 (-NO) 和超氧阴离子 (O2.-) 生成的平衡。我们将在血管水平上研究机制，以确定 SCD 如何诱导内皮细胞功能障碍。将 SCD 造血干细胞移植 (HSCT) 到基因工程小鼠中将用于测试低密度脂蛋白导致 SCD 血管舒张受损的替代假设。 SCD 的 HSCT 进入表达 apoA-1 缺陷 HDL 的 apoA-1 敲除小鼠中，将用于测试 D-4F 不会改善 HDL 功能以恢复血管舒张的替代假设。 D-4F 在改善预后方面的效用将在生存水平、缺血性损伤机制、器官病理学以及 HDL 与其他炎症介质相互作用的蛋白质组学方面进行测试。基于 D-4F 改善其他系统的血管舒张作用，我们的数据表明，靶向 HDL 可能是保护以慢性炎症状态为特征的疾病的血管功能的有效手段。通过这些研究，可以实现新的治疗方式来预防以氧化应激和炎症增加为特征的多种疾病的血管功能障碍。