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

该项目将开发量化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，该项目将研究填充眼球地球仪的液体的压力，也称为眼内压，其控制对于维持适当的视觉功能至关重要。慢性高眼内压与发展青光眼的高风险相关，青光眼是一种以视网膜神经节细胞丧失和永久性视力丧失为特征的进行性视神经病变。青光眼是世界范围内不可逆性失明的主要原因之一。尽管维持健康的眼内压水平的重要性，迄今为止，对于给定个体的最佳范围是什么的问题仍然没有答案。降低青光眼患者眼内压的药物治疗后结局、副作用和血流动力学影响的可变性，对预防数百万人的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，在该虚拟实验室中，可以定量研究眼内压，药物，血液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内压的最佳目标水平和实现该目标的治疗策略。 发展一个虚拟实验室来研究眼生理和功能，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（约。长度比例：100微米），甚至下至穿过睫状突内的非色素上皮细胞的膜的离子交换剂（约100微米）。长度尺度：10 nm），而眼部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），有必要采用多尺度建模方法。该项目的主要挑战是：（i）在相差6个数量级的长度尺度上捕获眼生理学的基本生物物理特征，同时保持整个模型的解决方案是可负担的;（ii）在离散化多尺度问题时保留眼生理学的基本生物物理特征，以获得其近似数值解;（iii）用大型和综合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，模型开发被阐明为两个具体目标：（目标1）对眼内压药物与房水流量之间的关系进行多尺度建模，以从理论上研究对表现出不同临床状况的患者的降压疗效;（目标2）多尺度建模的房水流量和眼部灌注之间的关系，从理论上研究眼血流动力学和功能的变化，在患者呈现不同的临床条件。反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.