Mechanisms of Microvascular Response to Arterial Stiffening and Flow Pulsatility

描述(申请人提供)：尽管PI以前的研究大多与生物医学相关，但都是以工程师的方法来解决生物医学问题，专注于开发新的工程方法(即材料、流体设备、成像技术和机械调节)，从机械工程的角度处理体外组织，仅基于对生物医学状况的基本了解。拟议的培训机会将为PI提供关于血管病理学、细胞信号转导、动物和临床实验的深入知识，以及在血管医学方面的成像、流体动力学和机械生物学方面的额外知识。这里提出的职业发展计划将极大地帮助PI在流动动力学、细胞分子生物学和血管医学的交叉点上的跨学科领域成长。动脉硬化被认为是心血管事件的一个重要因素，动脉血压升高是动脉硬化的直接结果，已被用于指导各种系统性血管疾病的药物治疗。研究项目的总体假设是，大动脉僵硬的增加有助于远端肺动脉结构和功能的改变，这是肺动脉高压的特征，而硬化的动脉通过调节血流脉动性在血管疾病中发挥这样的致病作用，从而导致和/或持久的PA远端循环中的炎症和血栓形成。为了验证这一假说，我们将研究三个具体目标：(1)确定分级肺血管系统中肺动脉僵硬和血流脉动之间的关系；(2)确定血流脉动对PA内皮细胞功能激活的影响；以及(3)确定血流诱导内皮细胞激活的分子机制。相关性(见说明)：这项研究计划将探索一种新的机制，以提高对肺血管疾病的理解。对这一机制的深入了解可能有助于开发新的诊断和治疗策略，从而提高受影响患者的生活质量和存活率。(摘要结束)

DESCRIPTION (provided by applicant): While much of the Pi's previous research has been peripherally related to biomedicine, it was all done as an engineer's approach to solve biomedical problems, focusing on development of new engineering approaches (i.e. materials, fluidic device, imaging techniques, and mechanical conditioning) to tackle tissue in vitro from a viewpoint of mechanical engineering, based on only a basic understanding of biomedical situation. The proposed training opportunity would provide the PI with an in-depth knowledge of vascular pathology, cell signal transduction, animal and clinical experimentation, as well as added knowledge in imaging, fluid dynamics and mechanobiology in the context of vascular medicine. The career development plan proposed here will greatly help the PI grow in a trans-disciplinary field at the intersection of flow dynamics, cell molecule biology, and vascular medicine. Arterial stiffening is recognized as an important factor of cardiovascular events and increased arterial pulse pressure, a direct consequence of stiffening, has been used to guide pharmaceutical treatment for a variety of systemic vascular diseases. The overall hypothesis of the research project is that increased stiffness of large pulmonary arteries contributes to structural and functional alterations in distal pulmonary arteries, characteristics of pulmonary arterial hypertension, and stiffened arteries play such a pathogenic role in vascular diseases via the modulation of flow pulsatility which causes and/or perpetuates inflammation and thrombosis in the distal PA circulation. To test this hypothesis, three specific aims will be studied: (1) Determine the relationship between pulmonary arterial stiffness and flow pulsatility in hierarchical pulmonary vasculature; (2) Determine effects of flow pulsatility on functional activation of PA endothelial cells; and (3) Determine the molecular mechanisms in flow-induced endothelial activation. RELEVANCE (See instructions): This research program will explore a new mechanism to improve understanding pulmonary vascular diseases. Insights into the mechanism may facilitate development of novel diagnostic and therapeutic strategies that offer an improved quality of life and increased survival rate of affected patients. (End of Abstract)