Mechanisms of Microvascular Response to Arterial Stiffening and Flow Pulsatility

描述（由申请人提供）：虽然Pi之前的大部分研究都与生物医学有关，但它都是作为工程师解决生物医学问题的方法而完成的，重点是从机械工程的角度开发新的工程方法（即材料，流体装置，成像技术和机械调节）来解决体外组织，仅基于对生物医学情况的基本了解。拟议的培训机会将使PI深入了解血管病理学、细胞信号转导、动物和临床实验，以及血管医学背景下的成像、流体动力学和机械生物学方面的知识。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交叉的跨学科领域中成长。动脉硬化被认为是心血管事件的重要因素，动脉脉压升高是硬化的直接后果，已被用于指导各种系统性血管疾病的药物治疗。该研究项目的总体假设是，大肺动脉僵硬度的增加导致远端肺动脉的结构和功能改变，肺动脉高压的特征，并且硬化的动脉在血管疾病中发挥这样的致病作用，通过调节血流脉动，导致和/或使远端肺动脉循环中的炎症和血栓形成持续存在。为了验证这一假设，将研究三个具体目标：(1)确定分层肺血管中肺动脉硬度和血流脉动之间的关系；(2)确定血流脉动性对PA内皮细胞功能激活的影响；(3)确定血流诱导内皮细胞活化的分子机制。相关性（见说明）：本研究项目将探索一种新的机制，以提高对肺血管疾病的认识。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，从而改善患者的生活质量，提高患者的存活率。（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)