Vascular mimetics to study inflammation and atherosclerosis

描述(申请人提供)：内脏肥胖症与高甘油三酯富脂蛋白(TGRL)和低高密度脂蛋白有关。这些人通常患有代谢综合征，并面临更高的动脉粥样硬化风险。高饱和脂肪饮食通过结合和摄取TGRL导致动脉斑块的形成，TGRL穿透血管壁，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体外系统，模拟动脉粥样硬化形成中的这些早期炎症事件。高脂饮食的影响是通过重复将培养的主动脉内皮细胞暴露于新鲜从人血浆中分离出来的天然餐后TGRL来模拟的。我们的主要假设是，天然的未经修饰的TGRL通过一条不同于氧化脂蛋白和清道夫受体的途径，通过低密度脂蛋白受体启动的途径放大细胞因子介导的炎症。内皮功能障碍与低切应力和血流紊乱的血管区域有关，这些区域是脂质堆积和单核细胞募集的部位，两者都加速了动脉粥样硬化的炎症轴。应用系统生物工程方法在定义的切应力下在细胞和分子水平上研究这一过程，具体有三个目的：1)利用血管模拟流道系统，确定人主动脉内皮细胞如何重复暴露于TGRL素以增强血管炎症和动脉粥样硬化。2)在明确的流体切应力条件下，从血管内皮细胞基因转录和蛋白表达水平分析动脉粥样硬化形成过程中的炎症事件。3)探讨血管模拟流道中单核细胞向致动脉内皮细胞募集的分子机制。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脂蛋白如何作为促炎介质，将平衡从健康的内皮转移到致动脉粥样硬化的内皮。 很少有研究关注动脉粥样硬化的最早事件，即内皮细胞屈服于高脂血症，降低其正常防御能力以延缓炎症。这项拟议中的研究的一个重要成果将是开发一个芯片上的实验室，来测量一个人饭后脂质的炎症潜力。这将反映一个人的代谢状况，并与他们患动脉粥样硬化和心脏病的倾向相关。

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.