Linking Spatial Variations Shear Stress-Oxidative Stress

连接空间变化剪切应力-氧化应力

• 批准号: 7145578
• 负责人: Tzung K Hsiai
• 金额: $ 40.01万
• 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/7145578
• 关键词: NAD(P)H dehydrogenase; aorta; atherosclerosis; atherosclerotic plaque; bioengineering /biomedical engineering; biosensor device; biotechnology; computer simulation; free radical oxygen; hemodynamics; hypercholesterolemia; laboratory rabbit; low density lipoprotein; molecular pathology; nitric oxide; nitric oxide synthase; oxidative stress; peroxynitrites; posttranslational modifications; shear stress; vascular endothelium

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；但是，它的表现往往是焦点和古怪的。已知剪切应力将NADPH氧化酶活性作为内皮超氧化物产生（O2-。）的来源。微电动机械系统（MEMS）提供了一种空间分辨率，可与单独伸长的内皮细胞和71 kHz处的时间分辨率相当，从而允许研究机制，从而调查了剪切应力的空间和时间变化，从而调节氧化剂应力介导的介导的反应。我们的工作假设是，在动脉分叉，中度至高剪切应力的区域在流动保持单向和轴向比对的经历相对较少的氧化应激。相比之下，反应性氧（ROS）的过量产生在很大程度上在相对低剪切应力，流动分离和脱离斧头排列和单向流动曲线的区域发展。我们建议分叉时剪切应力的空间变化调节02-的相对产生。或ROS和一氧化氮或活性氮种（RNS）产生。在振荡性剪切应力的动脉分叉中，O2的增加。-生产相对于无生产的产量可能会通过形成有效的氧化剂，过氧亚硝酸盐（ONOO-）而不会限制生物利用度。为了将MEMS传感器与我们的假设接口，我们提出以下三个目的：目标1。证明MEMS传感器提供空间分辨率，以在3-D对称分叉模型中解决剪切应力中的圆周变化。目标2。确定新西兰白色（NZW）兔子主动脉中的剪切应力中空间变化对剪切应力的特定区域的影响。目标3。阐明剪切应力中的空间和时间变化调节内皮的机制。没有和o2-。生产和随后的动脉粥样硬化LDL修饰。新的剪切应力传感技术可以应用于体内测量值，这些测量对于验证迄今为止细胞系统和体外发现的发现至关重要。 MEMS技术在兔子体内研究中的进一步开发和应用将是该项目的主要目标。