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会损害血管舒张的机制。该实验室的最新报道表明，在两种不同的血管疾病 - 染料胆固醇血症和镰状细胞病（SCD）的不同鼠模型中，ApoA-L模拟物4F显着改善了内皮和eNOS依赖性血管舒张。基于ApoA-L Mimetics设计以提高HDL功能，我们假设氧化应激和炎症会诱导HDL功能障碍，从而损害血管舒张。在此应用中，我们将在疾病状态和鼠模型中检验该假设，其血管功能障碍与炎症相比，与高脂血症，镰状细胞病（SCD）更紧密相关。尽管SCD主要是一种遗传疾病，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作用。该应用调查了以下概念，即炎症通过确定可恶的红细胞如何提高新的“犯罪中的伴侣”来诱导血管疾病来损害血管功能障碍。该应用程序的目的是确定炎症，HDL功能和促炎性脂质之间的相互作用，以期确定与可恶的红细胞合作以损害血管舒张的其他下游“伴侣”。我们将研究急性相蛋白，促炎HDL，促炎脂质和黄嘌呤氧化酶对转基因SCD小鼠血管功能的作用。严重和非严重SCD患者和对照组的血浆生物测定将用于识别和对潜在的伴侣进行损害和损害血管舒张并改变一氧化氮（-NO）和超氧化物阴离子（O2.-）在容器壁中的平衡。将在血管水平研究机制，以确定SCD如何诱导内皮细胞功能障碍。 SCD的造血干细胞移植（HSCT）将用于测试低密度脂蛋白有助于SCD中血管舒张受损的替代假设。 SCD的HSCT进入APOA-L基因敲除小鼠，该小鼠表达ApoA-L缺陷HDL将用于测试替代假设，即D-4F不能改善HDL功能以恢复血管舒张。 D-4F在改善预后的效用将在生存水平，缺血性损伤的机制，器官病理学的机制和HDL与其他炎症介体相互作用的蛋白质组学水平上进行测试。根据D-4F改善其他系统中的血管舒张，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中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，以防止各种疾病中的血管功能障碍，其特征是氧化应激和炎症的增加。