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，目前影响着超过 1000 万美国人，并且随着人口老龄化以及肥胖和糖尿病发病率的增加，这种疾病预计将变得更加普遍。 PAD 是由主要全身动脉（例如为腿部供血的股动脉）阻塞（通常由于动脉粥样硬化）引起的。 由于输送到小腿和足部的血液和氧气减少，PAD 患者在行走时经常会出现疼痛，进而发展为休息时疼痛，最终导致组织损失，需要进行手术移植，或者在严重的情况下需要截肢。 除了患者生产力下降和生活质量下降外，PAD 每年的医疗费用估计为 160-3000 亿美元。 目前，FDA 只批准了两种药物用于治疗 PAD 相关的步行障碍，而且两种治疗的效果都很差。 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，推动了这项研究工作。 理论和实验相结合的模型将用于设计更优化的实验，提供一种机制来理解不同血管段内适应动脉闭塞的重要性，并协助设计更成功的 PAD 疗法。流量下降，然后是短暂（分钟）、陡峭的流量增加，然后逐渐（几小时到几天）流量增加。然而，在严重闭塞后，脉管系统调节流量的能力会显着改变，从而阻止正常灌注的完全恢复。 据观察，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）是对主要动脉闭塞的反应，但每种适应的相对作用和时间尚不清楚，因此很难推断出最佳策略用于血流补偿。 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脉管系统的影响。 来自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根据影响血管直径和数量的机械因素来捕获主要动脉闭塞后的短期和长期血流动态。 此类工作将通过确定治疗药物的正确靶点和时机来真正改变目前对外周动脉疾病的认识，从而有助于恢复 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这种跨学科研究工作的直接接触机会，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: 2021-10
• 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

Heterogeneity of Ocular Hemodynamic Biomarkers among Open Angle Glaucoma Patients of African and European Descent

非洲和欧洲裔开角型青光眼患者眼部血流动力学生物标志物的异质性

• DOI: 10.3390/jcm12041287
• 发表时间: 2023-02-01
• 期刊: Journal of Clinical Medicine
• 影响因子: 3.9
• 作者: B. Siesky;A. Harris;A. V. Verticchio Vercellin;J. Arciero;Brendan C. Fry;G. Eckert;G. Guidoboni;F. Oddone;G. Antman
• 通讯作者: G. Antman

Retinal oximetry in glaucoma: investigations and findings reviewed

青光眼的视网膜血氧饱和度：调查和结果回顾

• DOI: 10.1111/aos.14397
• 发表时间: 2020-01
• 期刊: Acta Ophthalmologica
• 影响因子: 3.4
• 作者: Shughoury, Aumer;Mathew, Sunu;Arciero, Julia;Wurster, Patrick;Adjei, Susuana;Ciulla, Thomas;Siesky, Brent;Harris, Alon
• 通讯作者: Harris, Alon

Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site

模拟基于 Treg 的移植排斥疗法的潜力：剂量、时间和蓄积位点的影响

• DOI: 10.3389/ti.2022.10297
• 发表时间: 2022
• 期刊: Transplant International
• 影响因子: 3.1
• 作者: Lapp, Maya M.;Lin, Guang;Komin, Alexander;Andrews, Leah;Knudson, Mei;Mossman, Lauren;Raimondi, Giorgio;Arciero, Julia C.
• 通讯作者: Arciero, Julia C.

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: 2023-03
• 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