BIOENGINEERING-BIOLOGICAL STUDY OF ARTERIAL DISEASE

拟议的重建项目的目的是进一步加强我们的 了解血液动力学在动脉粥样硬化形成中的作用; 特别是为了阐明血流动力学 ic/生物力学力调节转胞吞和细胞 血管壁的反应。 多学科研究团队 联合各方力量，采取综合办法， 陈述的目标。 我们的研究计划是围绕一部小说展开的， 可靠的体外脉动灌注装置， 新鲜切除的动物和人体血管（动脉和静脉）， 明确的血液动力学。 该设备的一个重要特点是 血液动力学参数（例如，管腔内压力， 跨壁压、脉压、流速等）可以 个体变化和生物/生物力学反应的 血管壁进行了详细研究。 我们的假设是- 明确的、真实的体外血流动力学提供了一种 在这样的环境中，我们能够从根本上进行研究， 血液动力学力量如何影响 疾病的过程。 我们的研究将解决的具体问题包括： i）为什么静脉移植物在缝入动脉时可能“失败” 循环;特别是哪些动脉血液动力学参数 调节静脉的正常代谢和细胞反应; ii） 细胞代谢、结构和功能如何受到 “高”与“低”剪切应力; iii）细胞骨架是否 对血流动力学/生物力学力的适应有助于 体内动脉粥样硬化形成的特征性局部性质; iv）如果 血流动力学通过激活细胞外基质重组 改变动脉壁代谢; v）如果血液动力学（例如， 高血压）加速脂质积聚和细胞 斑块部位或附近的代谢与无病变 vi）哪些细胞类型在LDL降解中最活跃， 人动脉的动脉粥样硬化和非动脉粥样硬化部分 以及哪些受体（如果有的话）参与了这一过程 细胞摄取;以及，vii）“疾病易感”与 “抗病”动脉的功能不同， 上述参数响应于血液动力学。 据我们所知，这种综合办法， 系统地改变个体血液动力学参数和测量 血管壁对这些血流动力学的生物反应 变量，在其他生物工程方案中不可用， 马克在理解 血液动力学和动脉粥样硬化形成。

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.