CAREER: Integrating Theory and Experiment to Assess the Contribution of Distinct Vascular Segments in Arterial Insufficiency

外周动脉疾病（PAD）是目前影响超过1000万美国人的主要健康问题，随着人口老龄化以及肥胖和糖尿病发病率的增加，这种疾病预计会变得更加普遍。PAD是由主要全身动脉阻塞（通常是由于动脉粥样硬化）引起的，例如向腿部供血的股动脉。由于向小腿和足部输送的血液和氧气减少，PAD患者通常在行走时出现疼痛，并在休息时发展为疼痛，最终导致组织丢失，需要手术移植，严重者需要截肢。除了生产力下降和患者生活质量下降外，PAD每年的医疗保健费用估计为1600 - 3000亿美元。目前，只有两种药物被FDA批准用于治疗pad相关的行走障碍，而且这两种治疗方法的效果都很低。由于缺乏足够的数据和对不同血管适应对闭塞后恢复正常血流的影响的理解，促使了这项研究工作。理论和实验相结合的模型将用于设计更优化的实验，为理解不同血管段动脉闭塞适应的意义提供机制，并协助设计更成功的PAD治疗方法。主动脉闭塞后，血流立即下降，随后短暂（几分钟），血流急剧增加，然后逐渐（几小时到几天）血流增加。然而，血管调节血流的能力在严重闭塞后明显改变，阻止了正常灌注的完全恢复。血管适应，如新血管形成（血管生成）和现有血管生长（动脉生成），已被观察到发生在对主要动脉闭塞的反应中，但每种适应的相对作用和时间尚不清楚，因此很难推断出血流补偿的最佳策略。在这个项目中，将开发一个数学模型来预测主动脉闭塞后短期（急性）和长期（慢性）血管适应如何影响血流。这项工作将使用一个多尺度微分方程模型来耦合急性和慢性时间尺度的动力学，并评估血流动力学和代谢刺激对闭塞后侧枝和远端微血管的影响。小鼠后肢的实验数据将用于优化模型参数。迄今为止，还没有理论模型能够基于影响血管直径和数量的机械因素捕捉到主动脉闭塞后的短期和长期血流动态。这样的工作将真正改变目前对外周动脉疾病的认识，通过确定正确的靶点和治疗药物的时机，将有助于恢复PAD患者的正常灌注。该项目还为高中生、本科生和研究生提供了直接接触这一跨学科研究成果的机会，从而促进后代对STEM学科的学习，增强我国的科学文化。

Peripheral arterial disease (PAD) is a major health problem that currently affects more than 10 million Americans and that is expected to become even more prevalent with the aging of the population and increased incidence of obesity and diabetes. PAD is caused by a blockage (often due to atherosclerosis) of a major systemic artery such as the femoral artery that supplies blood to the leg. Due to reduced blood and oxygen delivery to their calf and foot, PAD patients often develop pain when walking that progresses to pain at rest and eventual tissue loss, requiring surgical grafts or, in severe cases, amputation. In addition to lost productivity and reduced quality of life for patients, the annual health care costs for PAD are estimated to be 160-300 billion dollars. Currently, only two medications have been approved by the FDA for treating PAD-associated walking impairment, and both treatments are minimally effective. The lack of sufficient data and understanding of the impact of different blood vessel adaptations on restoring normal blood flow following an occlusion motivates this research work. A combined theoretical and experimental model will be used to design more optimal experiments, provide a mechanism for understanding the significance of adaptations to arterial occlusion within distinct vascular segments, and assist in designing more successful PAD therapies.After a major arterial occlusion there is an immediate drop in flow, followed by a short (minutes), steep flow increase and then a gradual (hours to days) flow increase. However, the ability of the vasculature to regulate flow is significantly altered following a major occlusion, preventing full restoration of normal perfusion. Vascular adaptations such as new vessel formation (angiogenesis) and existing vessel growth (arteriogenesis) have been observed to occur in response to a major arterial occlusion, but the relative roles and timing of each adaptation are unclear, making it difficult to extrapolate an optimal strategy for blood flow compensation. In this project, a mathematical model will be developed to predict how short- (acute) and long-term (chronic) vascular adaptations impact flow after a major arterial occlusion. The work will use a multi-scale differential equation model to couple the dynamics of the acute and chronic time scales and to assess the effects of hemodynamic and metabolic stimuli on the collateral and distal microvasculature following an occlusion. Experimental data from the mouse hindlimb will be used to optimize model parameters. To date, no theoretical model has been able to capture both the short and long term dynamics of flow following a major arterial occlusion based on mechanical factors affecting vessel diameter and number. Such work will truly transform the current understanding of peripheral arterial disease by pinpointing the correct targets and timing for therapeutic agents that will help to restore normal perfusion in PAD patients. The project also provides direct exposure of this interdisciplinary research work to high school, undergraduate, and graduate students, thereby promoting the study of STEM disciplines among future generations and enhancing the scientific culture of our nation.