Linking Spatial Variations in Shear Stress with Oxidative Stress

将剪切应力的空间变化与氧化应力联系起来

• 批准号: 7269503
• 负责人: Tzung K Hsiai
• 金额: $ 38.97万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7269503
• 关键词: 3-Dimensional; Address; Affect; Aorta; Arterial Fatty Streak; Atherosclerosis; Biochemical; Biological Availability; Blood Vessels; Cells; Characteristics; Code; Condition; Development; Endothelial Cells; Etiology; Experimental Designs; Figs - dietary; Goals; Homologous Gene; In Vitro; Investigation; Lead; Lesion; Link; Liquid substance; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Measurement; Mechanics; Mediating; Modeling; Modification; Molecular; Monitor; NADP; NADPH Oxidase; New Zealand; Nitric Oxide; Nitric Oxide Synthase; Nitrogen; Oryctolagus cuniculus; Oxidants; Oxidative Stress; Oxygen; Peroxonitrite; Physiological; Play; Post-Translational Protein Processing; Production; Purpose; Range; Reactive Nitrogen Species; Reactive Oxygen Species; Regulation; Relative (related person); Research Personnel; Resolution; Role; Source; Stress; Superoxides; System; Systemic disease; Technology; Testing; Therapeutic Intervention; Translational Protein Modification; Variant; Vascular Endothelium; Work; atherogenesis; base; experience; human NOS3 protein; in vivo; oxidation; programs; response; sensor; shear stress; spatial temporal variation

DESCRIPTION (provided by applicant): Atherosclerosis is a systemic disease; however, its manifestations tend to be focal and eccentric. Shear stress is known to regulate NADPH oxidase activities as a source of endothelial superoxide production (O2-.). The Micro Electro Mechanical Systems (MEMS) provide a spatial resolution comparable to the individually elongated endothelial cells and temporal resolution at 71 kHz that permits investigation of the mechanisms whereby spatial and temporal variations of shear stress regulate the oxidant stress-mediated responses. Our working hypothesis is that at arterial bifurcations, the regions of moderate to high shear stress where flow remains unidirectional and axially aligned experience relatively little oxidative stress. In contrast, excess production of reactive oxygen species (ROS) develops largely in regions of relative low shear stress, flow separation, and departure from axjally aligned and unidirectional flow profiles. We propose that the spatial variations in shear stress at bifurcations regulate the relative production of 02-. or ROS and nitric oxide or reactive nitrogen species (RNS) production. At arterial bifurcations where oscillatory shear stress is prevalent, the increase in O2.- production relative to NO production likely limits NO bioavailability through formation of the potent oxidant, peroxynitrite (ONOO-). To interface the MEMS sensors with our hypothesis, we propose following three aims: Aim 1. Demonstrate that MEMS sensors provide spatial resolution to resolve circumferential variations in shear stress in a 3-D symmetric bifurcation model. Aim 2. Determine the effects of spatial variations in shear stress on specific regions of vascular oxidative stress in the aortas of New Zealand White (NZW) rabbits. Aim 3. Elucidate the mechanism(s) by which spatial and temporal variations in shear stress regulate endothelial .NO and O2-. production and subsequent atherogenic LDL modifications. The new shear stress sensing technology can be applied to in vivo measurements that are critical to validating the findings so far in cell systems and in vitro. Further development and application of MEMS technology to in vivo studies in rabbits will be a major goal of this project.

描述（由申请人提供）： 动脉粥样硬化是一种全身性疾病；然而，其表现往往是集中且古怪的。已知剪切应力可调节 NADPH 氧化酶活性，作为内皮超氧化物产生 (O2-) 的来源。微机电系统 (MEMS) 提供与单独伸长的内皮细胞相当的空间分辨率和 71 kHz 的时间分辨率，从而可以研究剪切应力的空间和时间变化调节氧化应激介导的反应的机制。我们的工作假设是，在动脉分叉处，流动保持单向和轴向对齐的中度至高剪切应力区域经历相对较少的氧化应激。相比之下，活性氧 (ROS) 的过量产生主要发生在剪切应力相对较低、流动分离以及偏离轴向对齐和单向流动剖面的区域。我们提出分叉处剪切应力的空间变化调节 02- 的相对产量。或 ROS 和一氧化氮或活性氮 (RNS) 的产生。在振荡剪切应力普遍存在的动脉分叉处，O2.- 产量相对于 NO 产量的增加可能会通过形成强效氧化剂过氧亚硝酸盐 (ONOO-) 来限制 NO 的生物利用度。为了将 MEMS 传感器与我们的假设结合起来，我们提出了以下三个目标： 目标 1. 证明 MEMS 传感器提供空间分辨率来解决 3-D 对称分叉模型中剪切应力的周向变化。目标 2. 确定剪切应力的空间变化对新西兰白兔 (NZW) 主动脉血管氧化应激特定区域的影响。目标 3. 阐明剪切应力的空间和时间变化调节内皮细胞 .NO 和 O2- 的机制。产生和随后致动脉粥样硬化的低密度脂蛋白修饰。新的剪切应力传感技术可应用于体内测量，这对于验证迄今为止在细胞系统和体外的研究结果至关重要。进一步开发MEMS技术并将其应用于兔子体内研究将是该项目的主要目标。