Collaborative Research: Multiscale Modeling of Intraocular Pressure Dynamics and Its Role in Ocular Physiology and Pharmacology

合作研究：眼压动态的多尺度建模及其在眼生理学和药理学中的作用

• 批准号: 2021192
• 负责人: Alon Harris
• 金额: $ 7.68万
• 依托单位: Icahn School of Medicine at Mount Sinai
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-11-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2021192&HistoricalAwards=false
• 关键词: Collaborative; Research; Multiscale; Modeling; Intraocular

This project will develop quantitative methods to combat vision impairment, which is one of the most impactful factors affecting quality of life. Specifically, this project will study the pressure of the fluids filling the eye globe, also called intraocular pressure, whose control is crucial to maintain a proper visual function. Chronically high intraocular pressure is associated with high risk of developing glaucoma, a progressive optic neuropathy characterized by a loss of retinal ganglion cells and permanent vision loss. Glaucoma constitutes one of the leading causes of irreversible blindness worldwide. Despite the importance of maintaining healthy levels of intraocular pressure, to date, the question of what is its optimal range for a given individual remains unanswered. The variability in outcomes, side effects and hemodynamic impacts following medications that lower intraocular pressure in glaucoma patients poses an additional, and currently unresolved, challenge in preventing vision loss for millions of individuals. The PIs will address this critical need by utilizing the laws of physics to develop a virtual laboratory where the relationship between intraocular pressure, medications, hemodynamics and ocular function can be studied quantitatively, and the optimal target level for intraocular pressure and the therapeutic strategy to achieve it can be theoretically estimated by accounting for patient's specific conditions. The development of a virtual laboratory to study ocular physiology and function requires to account for multiple length scales simultaneously. Since the action of medications occurs at the cellular level (approx. length scale: 100 microns), even down to the ion exchangers across the membrane of the non-pigmented epithelial cells within the ciliary processes (approx. length scale: 10 nm), while the clinical assessments of ocular hemodynamics and function occur at the whole organ level (approx. length scale: 3cm), it is necessary to adopt a multiscale modeling approach. The main challenges of this project are: (i) capturing the essential biophysical features of ocular physiology across length scales that differ by 6 orders of magnitude, while maintaining the solution of the overall model affordable; (ii) preserving the essential biophysical features of ocular physiology when discretizing the multiscale problem in order to obtain its approximate numerical solution; (iii) validating the model predictions with a large and comprehensive clinical and experimental dataset. To best address these challenges and successfully complete this project, the model development is articulated into two specific aims: (Aim 1) Multiscale modeling of the relationship between aqueous humor flow and medications for intraocular pressure to theoretically investigate the hypotensive efficacy on patients presenting different clinical conditions; (Aim2) Multiscale modeling of the relationship between aqueous humor flow and ocular perfusion to theoretically investigate the changes on ocular hemodynamics and function in patients presenting different clinical conditions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目将开发定量方法来打击视力障碍，这是影响生活质量的最有影响力的因素之一。具体而言，该项目将研究充满眼球的流体的压力，也称为眼内压，其控制对于维持适当的视觉功能至关重要。慢性的眼内压与患青光眼发展的高风险有关，这是一种进行性视神经病变，其特征是视网膜神经节细胞丧失和永久视力丧失。青光眼构成了全球不可逆失明的主要原因之一。尽管迄今为止保持健康的眼内压力水平的重要性，但其最佳范围的问题仍然没有得到解答。在青光眼患者中降低眼内压的药物后，结局，副作用和血液动力学影响的变异性会带来额外的且目前尚未解决的挑战，可防止数百万个人的视力丧失。 PI将通过利用物理定律来开发一个虚拟实验室来满足这一关键需求，在该实验室中可以进行数量研究，在该实验室中，可以通过定量研究眼内压力，药物，血液动力学和眼功能之间的关系，以及眼内压力的最佳目标水平和治疗策略以通过计算患者的特定条件来实现理论上的估计。 研究眼生理学和功能的虚拟实验室的开发需要同时考虑多个长度尺度。由于药物的作用发生在细胞水平（大约长度：100微米），甚至直到纤毛过程中未斑点上皮细胞的整个膜上的离子交换器（大约长度比例：10 nm），而在整个器官级别（大约是在整个器官级别上）的临床评估是在整个器官水平上发生的。该项目的主要挑战是：（i）在长度尺度上捕获眼生理学的基本生物物理特征，而长度尺度上则相差6个数量级，同时保持整体模型负担得起的解决方案； （ii）在离散多尺度问题以获得其近似数值解决方案时，保留眼生理的基本生物物理特征； （iii）使用大型且全面的临床和实验数据集验证模型预测。为了最好地应对这些挑战并成功完成该项目，该模型开发被阐明为两个具体的目的：（目标1）水性幽默流量与对眼内压力的药物之间的关系进行多尺度建模，以便在理论上研究对出现不同临床状况的患者的低血压疗效； （AIM2）水性幽默流量与眼部灌注之间关系的多尺度建模，从理论上研究了具有不同临床状况的患者的眼动力学和功能的变化。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的智力和更广泛影响的评估来通过评估来支持的，这是值得的。

项目成果

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

Association Between Dietary Salt Intake and Open Angle Glaucoma in the Thessaloniki Eye Study.

• DOI: 10.1097/ijg.0000000000002044
• 发表时间: 2022-07-01
• 期刊: Journal of glaucoma
• 影响因子: 2

Biofluid modeling of the coupled eye-brain system and insights into simulated microgravity conditions

眼脑耦合系统的生物流体建模以及对模拟微重力条件的见解

• 发表时间: 2019
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Salerni, Fabrizia;Repetto, Rodolfo;Harris, Alon;Pinsky, Peter;Prud’homme, Christophe;Szopos, Marcela;Guidoboni, Giovanna
• 通讯作者: Guidoboni, Giovanna

Prevalence Rates and Risk Factors for Primary Open Angle Glaucoma in the Middle East.

• DOI: 10.18502/jovr.v16i4.9755
• 发表时间: 2021-10
• 期刊: Journal of ophthalmic & vision research
• 影响因子: 2
• 作者: Torabi R;Harris A;Siesky B;Zukerman R;Oddone F;Mathew S;Januleviciene I;Vercellin ACV
• 通讯作者: Vercellin ACV

A THEORETICAL STUDY OF AQUEOUS HUMOR SECRETION BASED ON A CONTINUUM MODEL COUPLING ELECTROCHEMICAL AND FLUID-DYNAMICAL TRANSMEMBRANE MECHANISMS

• DOI: 10.2140/camcos.2019.14.65
• 发表时间: 2019-01-01
• 期刊: COMMUNICATIONS IN APPLIED MATHEMATICS AND COMPUTATIONAL SCIENCE
• 影响因子: 2.1
• 作者: Sala, Lorenzo;Mauri, Aurelio Giancarlo;Harris, Alon
• 通讯作者: Harris, Alon