Vascular mimetics to study inflammation and atherosclerosis

研究炎症和动脉粥样硬化的血管模拟物

• 批准号: 7373827
• 负责人: Anthony G. Passerini
• 金额: $ 47.76万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373827
• 关键词: Acute; Address; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Apolipoproteins; Atherosclerosis; Binding; Bioinformatics; Biological Markers; Biological Models; Biomedical Engineering; Blood Vessels; Cell Adhesion Molecules; Central obesity; Cholesterol; Classification; Condition; Data; Diagnostic; Diet; Dietary Factors; Dietary Fats; Endothelial Cells; Endothelium; Equilibrium; Event; Exhibits; Family; Fatty acid glycerol esters; Functional disorder; Genes; Genetic Transcription; Goals; Heart Diseases; High Density Lipoproteins; Human; Hyperlipidemia; Hypertriglyceridemia; Image; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Integrins; Lead; Link; Lipids; Lipoprotein Binding; Lipoproteins; Liquid substance; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; MAP Kinase Gene; MAPK14 gene; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Microarray Analysis; Microfluidics; Molecular; Molecular Profiling; Outcome; Pathway interactions; Persons; Phenotype; Physiological; Plasma; Polymerase Chain Reaction; Process; Publications; Reporter; Risk; Role; Signal Pathway; Site; Surface; System; Testing; Therapeutic; Time; Triglycerides; Variant; Very low density lipoprotein; atherogenesis; cardiovascular disorder risk; chemokine; chemokine receptor; cytokine; exposed human population; lipid metabolism; lipoprotein triglyceride; macromolecular assembly; micro-total analysis system; mimetics; molecular scale; monocyte; oxidized low density lipoprotein; prognostic; protein expression; receptor; receptor binding; response; saturated fat; scavenger receptor; shear stress; small molecule; therapeutic target; tool; uptake; vascular inflammation

DESCRIPTION (provided by applicant): Visceral obesity is associated with high triglyceride rich lipoproteins (TGRL) and low HDL. These individuals typically suffer from metabolic syndrome and are at increased risk for atherosclerosis. Diets high in saturated fat lead to arterial plaque formation through binding and uptake of TGRL, which penetrate into the vascular wall and stimulate cytokine expression and recruitment of monocytes. We have developed an ex-vivo system that models these early inflammatory events in atherogenesis. The influence of a high-fat diet is mimicked by repetitively exposing aortic endothelium in culture to native postprandial TGRL that is freshly-isolated from human plasma. Our primary hypothesis is that native unmodified TGRL amplifies cytokine mediated inflammation via an LDL receptor initiated pathway that is distinct from that of oxidized lipoprotein and the scavenger receptor pathway. Endothelial dysfunction is associated with vascular regions of low shear stress and disturbed flow that are sites of lipid accumulation and monocyte recruitment, both of which accelerate the inflammatory axis of atherogenesis. A systems bioengineering approach is applied to study this process at the cell and molecular scale under defined shear stress as described in three Specific Aims: 1) To define how repetitive exposure of human aortic endothelial cells to TGRL primes for enhanced vascular inflammation and atherogenesis employing a vascular mimetic flow channel system. 2) To analyze the inflammatory events in atherogenesis at the level of gene transcription and protein expression by aortic endothelial cells under conditions of well defined fluid shear stress. 3) To identify the molecular mechanisms underlying monocyte recruitment to atherogenic endothelium in vascular mimetic flow channels. Our overall goal is to identify how dietary lipoproteins from healthy and metabolic syndrome subjects act as proinflammatory mediators in shifting the balance from healthy to atherogenic endothelium.Project Narrative: Few studies have focused on the earliest event in atherosclerosis when endothelium succumbs to hyperlipidemia and lowers its normal defenses to stave off inflammation. A significant outcome of the proposed studies would be to develop a lab on a chip that measures the inflammatory potential of an individual's lipids after a meal. This would reflect a person's metabolic profile and correlate with their propensity to develop atherosclerosis and heart disease.

描述（由申请人提供）：内脏肥胖与高甘油三酸酯富脂蛋白（TGRL）和低HDL有关。这些人通常患有代谢综合征，并且患有动脉粥样硬化的风险增加。高饱和脂肪的饮食通过结合和摄取TGRL导致动脉斑块形成，这些TGRL渗透到血管壁中并刺激细胞因子的表达和单核细胞的募集。我们已经开发了一个前体系，该系统在动脉粥样硬化中对这些早期炎症事件进行了建模。通过重复将培养物主动脉内皮暴露于从人血浆中新鲜分离的天然后TGRL，可以模仿高脂饮食的影响。我们的主要假设是，天然未修饰的TGRL通过LDL受体引发的途径与氧化脂蛋白和清道夫受体途径不同的途径进行了细胞因子介导的炎症。内皮功能障碍与低剪切应力和流动障碍的血管区域有关，这是脂质积累和单核细胞募集的部位，这两者都加速了动脉粥样硬化的炎症轴。如三个特定目的所述，在定义的剪切应力下，采用系统生物工程方法在细胞和分子尺度上研究该过程：1）定义如何重复暴露人主动脉内皮细胞对TGRL的重复暴露，以增强血管炎症和具有血管模拟模拟流通道系统的动脉粥样硬化。 2）在定义明确的液体剪切应力条件下，主动脉内皮细胞的基因转录水平和蛋白质表达水平的动脉粥样硬化中的炎症事件。 3）确定单核细胞募集的分子机制在血管模拟流动通道中的动脉粥样硬化内皮中。我们的总体目标是确定来自健康和代谢综合征受试者的饮食中脂蛋白如何作为促炎性介体的促进介质，从而将平衡从健康转变为动脉粥样硬化性内皮。项目叙述： 当内皮屈服于高脂血症并降低其正常防御措施以避免炎症时，很少有研究集中在动脉粥样硬化中最早的事件。拟议的研究的一个重大结果是在芯片上开发一个实验室，该实验可以测量进餐后个体脂质的炎症潜力。这将反映一个人的代谢特征，并与他们发展动脉粥样硬化和心脏病的倾向相关。