Vascular mimetics to study inflammation and atherosclerosis

描述（由申请人提供）：内脏型肥胖与高甘油三酯富脂蛋白（TGRL）和低HDL相关。这些人通常患有代谢综合征，患动脉粥样硬化的风险增加。高饱和脂肪饮食通过结合和摄取TGRL导致动脉斑块形成，TGRL渗入血管壁，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离体系统来模拟动脉粥样硬化发生过程中的这些早期炎症事件。通过将培养的主动脉内皮反复暴露于刚从人血浆中分离出来的餐后TGRL，模拟高脂肪饮食的影响。我们的主要假设是，原生未修饰的TGRL通过LDL受体启动的途径放大细胞因子介导的炎症，该途径与氧化脂蛋白和清扫剂受体途径不同。内皮功能障碍与低剪切应力和血流紊乱的血管区域有关，这些区域是脂质积累和单核细胞聚集的地方，两者都加速了动脉粥样硬化的炎症轴。系统生物工程方法应用于在定义的剪切应力下在细胞和分子尺度上研究这一过程，如以下三个具体目标所述：1)定义如何使用血管模拟血流通道系统将人主动脉内皮细胞反复暴露于TGRL中，以增强血管炎症和动脉粥样硬化。2)在明确的流体剪切应力条件下，从基因转录和蛋白表达水平分析主动脉内皮细胞在动脉粥样硬化中的炎症事件。3)探讨血管模拟血流通道中单核细胞向致动脉粥样硬化内皮募集的分子机制。我们的总体目标是确定健康和代谢综合征受试者的膳食脂蛋白如何作为促炎介质，将平衡从健康内皮转移到致动脉粥样硬化内皮。项目概述:

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.