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

职业：结合理论和实验来评估不同血管段对动脉供血不足的贡献

• 批准号: 1654019
• 负责人: Julia Arciero
• 金额: $ 59.93万
• 依托单位: Indiana University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1654019&HistoricalAwards=false
• 关键词: CAREER; Integrating; Theory; Experiment; Assess

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.

外周动脉疾病（PAD）是一个主要的健康问题，目前影响超过1000万美国人，预计随着人口老龄化和肥胖症和糖尿病发病率的增加，PAD将变得更加普遍。 PAD是由主要的体循环动脉（如向腿部供血的股动脉）的阻塞（通常是由于动脉粥样硬化）引起的。 由于向小腿和足部输送的血液和氧气减少，PAD患者在行走时经常出现疼痛，这种疼痛会发展为休息时的疼痛，并最终导致组织损失，需要手术移植，或者在严重的情况下截肢。 除了生产力损失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。 缺乏足够的数据和理解的影响，不同的血管适应恢复正常的血流闭塞后，激励这项研究工作。 一个理论和实验相结合的模型将被用来设计更优化的实验，提供一个机制，了解适应不同血管段内动脉闭塞的意义，并协助设计更成功的PAD therapeutic.在主要动脉闭塞后，流量立即下降，随后是一个短暂的（分钟），流量急剧增加，然后逐渐（小时至天）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，阻止了正常灌注的完全恢复。 已经观察到血管适应，如新血管形成（血管生成）和现有血管生长（动脉生成），以响应于大动脉闭塞而发生，但每种适应的相对作用和时间尚不清楚，因此难以外推血流补偿的最佳策略。 在该项目中，将开发一个数学模型来预测主要动脉闭塞后短期（急性）和长期（慢性）血管适应如何影响血流。 这项工作将使用多尺度微分方程模型来耦合急性和慢性时间尺度的动态，并评估血流动力学和代谢刺激对闭塞后的侧支和远端微血管的影响。 来自小鼠后肢的实验数据将用于优化模型参数。 到目前为止，没有理论模型已经能够捕获的短期和长期的动态流动的主要动脉闭塞的基础上影响血管直径和数量的机械因素。 这些工作将真正改变目前对外周动脉疾病的理解，通过精确定位治疗药物的正确靶点和时机，这将有助于恢复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工作的机会，从而促进了后代对STEM学科的研究，并增强了我们国家的科学文化。

项目成果

Metabolic Signaling in a Theoretical Model of the Human Retinal Microcirculation

人类视网膜微循环理论模型中的代谢信号传导

• DOI: 10.3390/photonics8100409
• 发表时间: 2021
• 期刊: Photonics
• 影响因子: 2.4
• 作者: Arciero, Julia;Fry, Brendan;Albright, Amanda;Mattingly, Grace;Scanlon, Hannah;Abernathy, Mandy;Siesky, Brent;Vercellin, Alice Verticchio;Harris, Alon
• 通讯作者: Harris, Alon

Metabolic blood flow regulation in a hybrid model of the human retinal microcirculation

人体视网膜微循环混合模型中的代谢血流调节

• DOI: 10.1016/j.mbs.2023.108969
• 发表时间: 2023
• 期刊: Mathematical Biosciences
• 影响因子: 4.3
• 作者: Albright, Amanda;Fry, Brendan C.;Verticchio, Alice;Siesky, Brent;Harris, Alon;Arciero, Julia
• 通讯作者: Arciero, Julia

Predicting Experimental Sepsis Survival with a Mathematical Model of Acute Inflammation

用急性炎症的数学模型预测实验性脓毒症生存率

• DOI: 10.3389/fsysb.2021.755913
• 发表时间: 2021
• 期刊: Frontiers in Systems Biology
• 作者: Barber, Jared;Carpenter, Amy;Torsey, Allison;Borgard, Tyler;Namas, Rami A.;Vodovotz, Yoram;Arciero, Julia
• 通讯作者: Arciero, Julia

Predicting retinal tissue oxygenation using an image-based theoretical model

• DOI: 10.1016/j.mbs.2018.08.005
• 发表时间: 2018-11-01
• 期刊: MATHEMATICAL BIOSCIENCES
• 影响因子: 4.3
• 作者: Fry, Brendan C.;Coburn, Ehren Brant;Arciero, Julia
• 通讯作者: Arciero, Julia