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

该项目将开发定量方法来对抗视力障碍，这是影响生活质量的最重要因素之一。具体来说，这个项目将研究填充眼球的液体压力，也称为眼内压，其控制对维持正常的视觉功能至关重要。慢性高眼压与发生青光眼的高风险相关，青光眼是一种进行性视神经病变，其特征是视网膜神经节细胞的丧失和永久性视力丧失。青光眼是世界范围内导致不可逆失明的主要原因之一。尽管维持健康的眼压水平很重要，但迄今为止，对于特定个体而言，其最佳范围是什么仍然没有答案。降低青光眼患者眼压的药物治疗的结果、副作用和血流动力学影响的可变性为数百万人预防视力丧失提出了额外的、目前尚未解决的挑战。pi将通过利用物理定律开发虚拟实验室来解决这一关键需求，在虚拟实验室中可以定量研究眼压，药物，血流动力学和眼功能之间的关系，并且可以通过考虑患者的具体情况从理论上估计眼压的最佳目标水平和实现该目标的治疗策略。开发研究眼生理和功能的虚拟实验室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上（大约）。长度尺度：100微米)，甚至到纤毛突内的非色素上皮细胞膜上的离子交换器（约100微米）。长度尺度：10 nm)，而眼血流动力学和功能的临床评估发生在整个器官水平（约10 nm）。长度尺度：3cm)，需要采用多尺度建模方法。该项目的主要挑战是：(i)捕捉眼生理学的基本生物物理特征，跨越6个数量级的长度尺度，同时保持整体模型的解决方案可承受；（ii）在离散多尺度问题以获得近似数值解时，保留眼生理学的基本生物物理特征；（iii）用大型和全面的临床和实验数据集验证模型预测。为了更好地应对这些挑战并成功完成本项目，该模型的开发有两个具体目标：（目标1）房水流量与眼压药物之间关系的多尺度建模，从理论上研究不同临床情况患者的降压效果；（目的2）建立房水流动与眼灌注关系的多尺度模型，从理论上探讨不同临床情况患者眼血流动力学和眼功能的变化。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.