Inflammation, Atherosclerosis and ApoA-I

炎症、动脉粥样硬化和 ApoA-I

基本信息

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
项目类别：
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

项目摘要

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）：加速动脉粥样硬化表现出复杂的发病机制，包括脂质的改变、涉及免疫系统的炎症状态。 HDL apoA-I 主要通过其从免疫细胞中组织和募集胆固醇以及含氧形式的胆固醇和磷脂的能力来防止这些变化，从而保护免疫细胞免受失调和细胞凋亡的影响。在当前的提案中，我们将研究 LDL 受体、apoA-I 双敲除 (DKO) 小鼠中免疫细胞胆固醇沉积、加速动脉粥样硬化以及响应致动脉粥样硬化饮食而产生自身免疫表型的分子机制。在之前的研究中，当 DKO 和 LDLr-/- (SKO) 小鼠被喂食致动脉粥样硬化饮食时，与 SKO 小鼠相比，DKO 小鼠的外周淋巴结 (LN) 和脾脏增大。 DKO LN 富含胆固醇酯 (CE)，并含有大量富含 CE 的 T、B、树突状细胞和巨噬细胞。 DKO 中 dsDNA 和氧化 LDL 的血浆抗体也增加，表明存在自身免疫表型。当饮食喂养的 DKO 小鼠在开始饮食时用 apoA-I 治疗时，LN 增大和 LN CE 积累都被“阻止”。无论膳食胆固醇水平如何，DKO 小鼠始终表现出比 SKO 小鼠更低的血浆胆固醇，但主动脉胆固醇沉积和炎症更大。因此，本提案的目标是使用 DKO 小鼠研究 apoA-I 1) 调节淋巴细胞中 CE 和氧甾醇积累和激活的机制，2) 改变加载 CE 的淋巴细胞的增殖和/或凋亡，3)影响饮食喂养的 DKO 小鼠动脉粥样硬化进展和消退过程中 T 细胞和 DC 对斑块浸润的贡献。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失调引发。我们提出的研究将调查解释 apoA-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的机制。这些研究可能会为控制加剧动脉粥样硬化的炎症过程的治疗干预提供新的目标。