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1000多万美国人的一个主要健康问题，预计随着人口老龄化和肥胖和糖尿病发病率的增加，这种问题将变得更加普遍。PAD是由主要的全身动脉阻塞(通常是由于动脉粥样硬化)引起的，例如供应腿部血液的股动脉。由于向小腿和脚输送的血液和氧气减少，PAD患者在行走时经常会出现疼痛，进而发展为休息时的疼痛和最终的组织丢失，需要手术移植或在严重情况下截肢。除了丧失生产力和降低患者的生活质量外，PAD每年的医疗保健成本估计为160-3000亿美元。目前，只有两种药物被FDA批准用于治疗与脚垫相关的行走障碍，而且这两种治疗方法的效果都很低。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了解促使了这项研究工作。理论和实验相结合的模型将被用来设计更优化的实验，提供一种机制来理解不同血管节段内适应动脉闭塞的重要性，并帮助设计更成功的PAD疗法。在主要动脉闭塞后，流量立即下降，随后是短暂(分钟)、陡峭的流量增加，然后是逐渐(几小时到几天)的流量增加。然而，血管系统调节血流的能力在严重闭塞后显著改变，阻止了正常血流的完全恢复。已经观察到血管适应，如新的血管形成(血管生成)和现有的血管生长(动脉生成)是对主要动脉闭塞的响应，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短期(急性)和长期(慢性)血管适应如何影响主要动脉闭塞后的血流。这项工作将使用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支和远端微血管系统的影响。来自小鼠后肢的实验数据将被用于优化模型参数。到目前为止，还没有一个理论模型能够基于影响血管直径和数量的机械因素来捕捉主要动脉闭塞后的短期和长期血流动力学。这些工作将通过确定正确的靶点和治疗药物的时机，真正改变目前对外周动脉疾病的理解，有助于恢复PAD患者的正常血流。该项目还向高中、本科生和研究生提供了这一跨学科研究工作的直接机会，从而促进了子孙后代对STEM学科的研究，并增强了我国的科学文化。

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.