Inflammation, Atherosclerosis and ApoA-I

炎症、动脉粥样硬化和 ApoA-I

• 批准号: 8206793
• 负责人: Mary G Sorci-Thomas
• 金额: $ 36.63万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206793
• 关键词: ATP-Binding Cassette Transporters; Affect; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Aorta; Apolipoprotein A-I; Apolipoproteins A; Apoptosis; Apoptotic; Arterial Fatty Streak; Arteries; Atherogenic Diet; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; CETP gene; Cause of Death; Cell Proliferation; Cell Separation; Cells; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol Homeostasis; Chronic; Complex; Coronary artery; Coronary heart disease; Data; Dendritic Cells; Deposition; Development; Diet; Dietary Cholesterol; Disease; Enlargement of lymph nodes; Excretory function; Exhibits; Functional disorder; Gene Expression; Glycerylphosphorylcholine; Glycoproteins; Goals; Heat shock proteins; High Density Lipoproteins; Human; Immune; Immune response; Immune system; Immunodeficient Mouse; In Vitro; Infiltration; Inflammation; Inflammatory; Interleukin-1 beta; Interleukins; Knock-out; Link; Lipids; Liquid Chromatography; Listeria monocytogenes; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Lymphocyte; Lymphoid; Mass Fragmentography; Mass Spectrum Analysis; Measures; Mediating; Messenger RNA; Molecular; Mus; Necrosis; Organ; Pathogenesis; Performance; Peripheral; Phenotype; Phosphatidylcholine-Sterol O-Acyltransferase; Phospholipids; Plasma; Play; Population; Process; Production; Publishing; Receptor Cell; Recombinants; Recruitment Activity; Regulatory T-Lymphocyte; Rheumatoid Arthritis; Risk; Risk Factors; Role; Self Tolerance; Signal Transduction; Site; Skin; Spleen; Splenomegaly; Sterol O-Acyltransferase; Study models; Systemic Lupus Erythematosus; T-Lymphocyte; Temperature; Testing; Therapeutic Intervention; Time; Tissues; Toll-like receptors; Transferase; Transforming Growth Factors; Triglycerides; Tumor Necrosis Factor-alpha; Very low density lipoprotein; cell growth; cytokine; fast protein liquid chromatography; feeding; gel electrophoresis; high risk; lymph nodes; macrophage; mouse model; oxidized low density lipoprotein; prevent; public health relevance; receptor; response; reverse cholesterol transport; scavenger receptor; trafficking

DESCRIPTION (provided by applicant): Accelerated atherosclerosis displays a complex pathogenesis including alterations in lipids, inflammatory state involving the immune system. HDL apoA-I protects against these changes mainly through its ability to organize and recruit cholesterol and oxygenated forms of cholesterol and phospholipids from immune cells protecting them from dysregulation and apoptosis. In the current proposal, we will investigate the molecular mechanisms responsible for immune cell cholesterol deposition, accelerated atherosclerosis and the development of an autoimmune phenotype in response to an atherogenic diet in LDL receptor, apoA-Idouble knockout (DKO) mice. In previous studies, when DKO and LDLr-/- (SKO) mice were fed an atherogenic diet, DKO mice developed enlarged peripheral lymph nodes (LNs) and spleens compared to SKO mice. DKO LN were enriched in cholesterol ester (CE) and contained expanded populations of CE enriched T, B, dendritic cells and macrophages. Plasma antibodies to dsDNA and oxidized LDL were also increased in DKO suggesting an autoimmune phenotype. Both LN enlargement and LN CE accumulation were "prevented" when diet-fed DKO mice were treated with apoA-I at the time the diet was initiated. Regardless of the level of dietary cholesterol, DKO mice consistently showed lower plasma cholesterol than SKO mice, yet greater aortic cholesterol deposition and inflammation. Therefore, the goal of this proposal is to use the DKO mouse to investigate the mechanisms by which apoA-I 1) modulates CE and oxysterol accumulation and activation in lymphocytes, 2) alters the proliferation and/or apoptosis of CE loaded lymphocytes, 3) affects the contribution of T cells and DC to plaque infiltration in both progression and regression of atherosclerosis in diet-fed DKO mice. PUBLIC HEALTH RELEVANCE: Atherosclerosis is a chronic inflammatory disease that is initiated by cellular cholesterol dysregulation at the vessel wall. Our proposed studies will investigate the mechanisms explaining the role of apoA-I in regulating lymphocyte cholesterol homeostasis, autoimmunity and atherosclerosis. These studies will likely provide new targets for therapeutic interventions to control the inflammatory processes that exacerbate atherosclerosis.

描述(由申请人提供)：加速的动脉粥样硬化表现为一种复杂的发病机制，包括血脂的改变，涉及免疫系统的炎症状态。高密度脂蛋白载脂蛋白A-I主要通过组织和招募免疫细胞中的胆固醇和氧化形式的胆固醇和磷脂来防止这些变化，保护免疫细胞免受失调和细胞凋亡的影响。在目前的方案中，我们将研究在低密度脂蛋白受体apoA-I双重敲除(DKO)小鼠中，导致免疫细胞胆固醇沉积、加速动脉粥样硬化和自身免疫表型发展的分子机制。在以前的研究中，当DKO和LDLR-/-(SKO)小鼠被喂食致动脉粥样硬化的食物时，DKO小鼠比SKO小鼠出现周围淋巴结(LNS)和脾的增大。DKO LN富含胆固醇酯(CE)，并含有大量富含CE的T、B细胞、树突状细胞和巨噬细胞。DKO患者血浆抗dsDNA抗体和氧化低密度脂蛋白抗体也升高，提示为自身免疫表型。当饮食喂养的DKO小鼠在开始饮食时用apoA-I治疗时，LN扩大和LN CE积聚都被“防止”。无论饮食中的胆固醇水平如何，DKO小鼠始终显示出比SKO小鼠更低的血浆胆固醇，但主动脉胆固醇沉积和炎症更多。因此，本研究的目的是利用DKO小鼠来研究apoA-I在饮食喂养的DKO小鼠动脉粥样硬化的进展和消退过程中，1)调节CE和氧固醇在淋巴细胞中的积聚和激活，2)改变CE负载的淋巴细胞的增殖和/或凋亡，3)影响T细胞和DC在斑块浸润中的作用。 公共卫生相关性： 动脉粥样硬化是一种慢性炎症性疾病，由血管壁细胞胆固醇调节失调引起。我们建议的研究将探讨载脂蛋白A-I在调节淋巴细胞胆固醇稳态、自身免疫和动脉粥样硬化中的作用机制。这些研究可能会为治疗干预提供新的靶点，以控制加剧动脉粥样硬化的炎症过程。