BIOENGINEERING-BIOLOGICAL STUDY OF ARTERIAL DISEASE

动脉疾病的生物工程生物学研究

• 批准号: 3348001
• 负责人: HARVEY S. BOROVETZ
• 金额: $ 17.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1991-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3348001
• 关键词: actins; artery occlusion; atherosclerosis; blood lipoprotein transport; carotid artery; catalase; cholesterol; cholesterol esters; dogs; fluorescence microscopy; hemodynamics; laboratory rabbit; lysophospholipase; mathematical model; model design /development; myosins; perfusion; radiotracer; scanning electron microscopy; tissue /cell culture

The aim of the proposed renewal project is to further our understanding of the role of hemodynamics in atherogenesis; in particular to elucidate mechanisms by which hemodynam ic/biomechanical forces modulate the transcytotic and cellular responses of the vessel wall. A multidisciplinary research team has joined forces in an integrated approach to accomplish our stated aims. Our research plan is built around a novel and reliable in vitro pulsatile perfusion apparatus which exposes freshly excised animal and human vessels (arteries and veins) to well-defined hemodynamics. An important feature of this device is that hemodynamic parameters (e.g., intraluminal pressure, transmural pressure, pulse pressure, rate of flow, etc.) can be individually varied and the biologic/biomechanical response of the vessel wall studied in detail. It is our hypothesis that the de- livery of defined, realistic hemodynamics in vitro provides an environment in which we are able to study, on a fundamental level, how hemodynamic forces influence molecular and cellular aspects of the disease process. Specific timely questions that our studies will address include: i) why vein grafts may "fail" when sewn into the arterial circulation; in particular which arterial hemodynamic parameter(s) modulate the normal metabolic and cellular response of veins; ii) how cellular metabolism, structure and function are influenced by "high" versus "low" shear stress; iii) whether cytoskeletal adaptation to hemodynamic/biomechanical forces contributes to the characteristicallyfocal nature of atherogenesis in vivo; iv) if hemodynamics initiate extracellular matrix reorganization by altering arterial wall metabolism; v) if hemodynamics (e.g., hypertension) accererates lipid accumulation and cellular metabolism at or adjacent to sites of plaque versus lesion free areas; vi) which cell types are most active in LDL degradation in atherosclerotic and non-atherosclerotic portions of human arteries perfused in vitro and which receptors, if any, are involved in this cellular uptake; and, vii) whether "disease susceptible" versus "disease resistant" arteries differ as a function of the aforementioned parameters in response to hemodynamics. To our best knowledge, this integrated approach in which we systematically vary individual hemodynamic parameters and measure the biologic response of the vessel wall to these hemodynamic variables, is unavailable in other bioengineering protocols and marks s important advance toward understanding the role of hemodynamics an atherogenesis.

拟议重建计划的目的是进一步发展我们的 了解血流动力学在动脉粥样硬化形成中的作用 特别是为了阐明血液动力学的机制 IC/生物机械力调节跨细胞和细胞 脉管壁的反应。一个多学科的研究团队 已经联合起来，以一种综合的方法来实现我们的 明确的目标。我们的研究计划是围绕一部小说和 可靠的体外脉动灌注仪，暴露在 新鲜切除的动物和人体血管(动、静脉) 明确的血流动力学。这款设备的一个重要特点是 血流动力学参数(例如，腔内压力， 跨壁压、脉搏压、流速等)可 个体差异和关节的生物/生物力学反应 对血管壁进行了详细的研究。我们的假设是- 明确的、真实的体外血流动力学提供了一种 我们能够从根本上研究的环境， 血流动力学力量如何影响血管的分子和细胞方面 疾病的过程。 我们的研究将解决的具体及时问题包括： 一)为什么静脉移植物在缝合到动脉中时会“失败” 循环；特别是哪个动脉血流动力学参数(S) 调节静脉的正常代谢和细胞反应；ii) 细胞的新陈代谢、结构和功能如何受到 “高”与“低”剪应力；iii)细胞骨架 对血流动力学/生物力学力量的适应有助于 体内动脉粥样硬化形成特有的焦点性质；四)如果 血流动力学通过以下途径启动细胞外基质重组 改变动脉壁代谢；v)如果血流动力学(例如， 高血压)加速脂质堆积和细胞 斑块部位或邻近部位的代谢与无斑块的代谢 区域；vi)哪些细胞类型在降解低密度脂蛋白方面最活跃 人体动脉的动脉硬化部和非动脉硬化部 在体外灌流，以及哪些受体，如果有的话，参与其中 细胞摄取；以及，vii)“疾病易感性”与 “抗病”动脉的功能不同于 上述参数对血流动力学的影响。 据我们所知，我们采用的这种综合方法 系统地改变个体血流动力学参数和测量 血管壁对这些血流动力学的生物学反应 在其他生物工程方案中是不可用的， 标志着S在理解 血液动力学是动脉粥样硬化的形成.