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: 8438143
• 负责人: Anthony G. Passerini
• 金额: $ 35.26万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438143
• 关键词: Acute; Adhesions; Affect; Antiatherogenic; Apolipoproteins; Arteries; Atherosclerosis; Biological Assay; Biological Markers; Biomechanics; Biomedical Engineering; Blood; Blood Vessels; CCL2 gene; Cardiology; Catheters; Cell Adhesion; Cell Adhesion Molecules; Cell Line; Cells; Central obesity; Chronic; Clinic; Clinical; Coronary Arteriosclerosis; Cues; Data; Development; Diagnosis; Diet; Dietary Fats; Dietary Supplementation; Disease; Down-Regulation; Endocytosis; Endothelial Cells; Endothelium; Equilibrium; Event; Exhibits; Exposure to; Fatty Acids; Fatty acid glycerol esters; Goals; Grant; Heart Diseases; Heel; Human; Hypertriglyceridemia; ITGAX gene; ITGB2 gene; Image; Individual; Inflammation; Inflammatory; Inflammatory Response; Integrin Binding; Integrin alpha4beta1; Integrins; Intervention; Link; Lipids; Lipoproteins; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolic syndrome; Metabolism; MicroRNAs; Microfluidics; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Patients; Pattern; Phenotype; Phosphotransferases; Plasma; Predisposition; Regulation; Relative (related person); Reporting; Risk; Risk Factors; Role; Sampling; Serum; Signal Pathway; Societies; System; TNF gene; Technology; Time; Tissue Sample; Triglyceride Metabolism; Triglycerides; Up-Regulation; Vascular Cell Adhesion Molecule-1; atherogenesis; base; cardiovascular disorder risk; cardiovascular risk factor; chemokine; clinical risk; cohort; cytokine; endoplasmic reticulum stress; human subject; in vivo; insight; metabolic abnormality assessment; metabolomics; micro-total analysis system; mimetics; molecular scale; monocyte; mortality; novel; novel strategies; particle; prevent; promoter; protein expression; public health relevance; response; saturated fat; shear stress; transcription factor; uptake

DESCRIPTION (provided by applicant): This competitive renewal is focused on atherosclerosis, the primary cause of mortality in Western society. Our studies and others reveal that arterial plaque formation closely correlates with visceral obesity and concomitant high levels of circulating triglyceride rich lipoproteins (TGRL), especially associated with diets high in saturated fat. Over the tenure of this grant, we have developed an ex-vivo model of early inflammatory events of atherogenesis by studying blood monocytes and TGRL isolated postprandial from plasma of subjects ranging from healthy to obese and hypertriglyceridemic. By examining their interaction with low passage cultured human aortic endothelial cells (HAEC), we have reported that acute exposure to TGRL augmented cytokine- induced VCAM-1 expression and monocyte recruitment under shear stress. In subjects exhibiting high cardiovascular risk (i.e. high postprandial TGRL and abdominal obesity) we detected increased foamy monocytes in blood and correlated this with integrin activation and arrest to VCAM-1, as quantified in our vascular mimetic shear flow assay. These data provide a framework for quantifying an individual's atherogenic susceptibility. Our primary hypothesis is that we can delineate the metabolic pathways that go awry and correlate these with biomarkers of endothelial and monocyte inflammation measured ex vivo in order to provide valuable clinical insight in assessing an individual's risk for developing inflammation-mediated coronary artery disease. A systems bioengineering approach is applied to study metabolic and biomechanical responses at the cell and molecular scale using real time imaging and novel microfluidic technology in three specific aims: 1) Quantify an individual's metabolic profile following a high-fat meal in terms of the inflammatory capacity of their TGRL. 2) Delineate how TGRL signaling pathways regulate an atherogenic profile in aortic endothelium. 3) Identify the earliest events linked to hypertriglyceridemia and obesity that increase monocyte proclivity to arrest on atherogenic endothelium using a lab-on-a-chip assay. Our overall goal is to develop assays that pinpoint the extent to which dietary lipoproteins from healthy and metabolic syndrome subjects are exerting pro- inflammatory effects that shift the balance from healthy to atherogenic vasculature.

描述（由申请人提供）：这种竞争性更新集中于动脉粥样硬化，这是西方社会死亡率的主要原因。我们的研究和其他研究表明，动脉斑块的形成与内脏肥胖和伴随的高水平密切相关 循环甘油三酸酯富脂蛋白（TGRL），尤其是与饱和脂肪高的饮食有关。在这笔赠款的任期内，我们通过研究血液单核细胞和TGRL分离的植物炎性事件的前体炎症事件模型，从健康到肥胖和高甘油酸酯的受试者的血浆中分离出来。通过检查它们与低通道培养的人主动脉内皮细胞（HAEC）的相互作用，我们报告说，急性暴露于剪切应力下的细胞因子诱导的VCAM-1表达和单核细胞募集。在表现出高心血管风险（即餐后TGRL和腹部肥胖症）的受试者中，我们检测到血液中泡沫状单核细胞的增加，并将其与整合素激活相关，并与VCAM-1进行抗管，并与VCAM-1进行了停止，在我们的血管模拟剪切流量测定中进行了量化。这些数据提供了量化个人动脉粥样硬化易感性的框架。我们的主要假设是，我们可以描述出偏差并将其与内皮细胞和单核细胞炎症的生物标志物相关的代谢途径，这些途径被测量的离体测量，以便在评估个人患炎症介导的冠状动脉疾病的风险方面提供有价值的临床见解。采用系统生物工程方法用于研究细胞和分子尺度上的代谢和生物力学反应，使用实时成像和新颖的微流体技术以三个具体目的：1）用TGRL的炎症能力来量化个人的代谢特征。 2）描述TGRL信号通路如何调节主动脉内皮中的动脉粥样硬化特征。 3）确定与高甘油三酯血症和肥胖相关的最早事件，这些事件增加了使用实验室的芯片测定法，增加了单核细胞倾向以在动脉粥样硬化的内皮上停滞。我们的总体目标是开发测定法，以指出健康和代谢综合征受试者的饮食脂蛋白在多大程度上发挥促炎性作用，从而将平衡从健康变为动脉粥样硬化性脉管系统。