The role of iris biomechanics and sex differences in primary angle-closure glaucoma

原发性闭角型青光眼 (PACG) 是全球范围内不可逆性失明的一个重要原因，影响 c. 1700 万人。 PACG 在女性中更为普遍；不幸的是，造成这种不平等的根本原因 患病率未知。性别以外的因素，例如前房的解剖缺陷、种族和 年龄，与 PACG 相关，解剖缺陷是公认的主要临床标准 评估 PACG 风险。然而，多项临床试验表明，这种解剖学因素的效果出奇的差。 PACG 发展的预测因素，表明 PACG 中还涉及其他未考虑的因素。 PACG的病理生理机制与虹膜的生物力学密切相关。具体来说，在 瞳孔阻滞 (PB) 是 PACG 的一个关键特征，虹膜和晶状体之间的接触会产生压力梯度 前房和后房之间。随后，PB 导致流出途径闭塞（即， 虹膜前部变形导致闭角[AC]），并伴有眼压升高和 潜在的青光眼视力丧失。我们和其他人已经证明，通过使用瞳孔反射（例如，触发 通过光），人们可以非侵入性地评估虹膜的生物力学特性。有趣的是，在患者中 根据 PACG 的历史，虹膜比对照组更僵硬。然而，虹膜生物力学在诱导 AC 中的作用 PACG 未知。 我们的中心假设是，虹膜生物力学在开发基于 PACG 的过程中发挥着至关重要的、未被重视的作用。 虹膜变形与虹膜生物力学特性之间的自然联系。因此，这个亲 项目目标是通过评估虹膜生物群落来研究虹膜生物力学在 PACG 中的作用 AC 和 PB 的机械特性和力学。此外，我们将调查性别依赖性差异 虹膜生物力学及其在使女性患 PACG 的风险较高中的潜在作用。 该项目的具体目标 (SA) 是： SA1 - 研究虹膜生物力学特性的性别差异 在兔子身上使用体内/离体混合方法（K99 指导阶段）。 SA2 - 调查性别差异 使用体内和离体（尸体）分析人类虹膜的生物力学特性。 SA3 - 调查生物- 诱发 AC 和 PB 所需的机械条件及其与性别和 AC 病史的关系 (R00)。这些 研究将提供对 PACG 病理生理学的更好理解，并提供独特的机会 结合工程、基础科学和临床研究来解决重大的公共卫生问题。 在指导阶段，申请人将学习多种基础技术，包括体内动物 兔子研究、活动（肌肉）组织的生物力学分析、组织学、OCT 成像和人体亚 项目研究。此外，他还将通过各种机制大幅拓展自己的专业培训。的 在指导阶段学到的技能和技术将建立在申请人的组织生物背景之上 机械师，让他能够追求成功且有影响力的独立学术生涯。

Primary angle-closure glaucoma (PACG) is a significant cause of irreversible blindness worldwide, affecting c. 17M people. PACG is more prevalent among women; unfortunately, the underlying reasons for this unequal prevalence are unknown. Factors other than sex, such as anatomical deficits in the anterior chamber, race, and age, are associated with PACG, with anatomical deficits being the accepted primary clinical criteria used to assess PACG risk. However, several clinical trials have shown that such anatomical factors are surprisingly poor predictors of PACG development, indicating the involvement of other unaccounted factors in PACG. The pathophysiological mechanisms of PACG are closely related to the biomechanics of the iris. Specifically, in pupillary block (PB), a key feature of PACG, contact between the iris and the lens induces a pressure gradient between the anterior and posterior chambers. Subsequently, PB leads to occlusion of the outflow pathway (i.e., angle closure [AC]) by anterior deformation of the iris, with associated elevation of intraocular pressure and potential glaucomatous vision loss. We and others have shown that by using pupillary reflexes (e.g., triggered by light), one can non-invasively evaluate the biomechanical properties of the iris. Interestingly, in patients with a history of PACG, the iris is stiffer compared to controls. However, the role of iris biomechanics in inducing AC and PACG is unknown. Our central hypothesis is that iris biomechanics plays a crucial, unappreciated role in developing PACG, based on the natural connection between iridial deformations and iridial biomechanical properties. Therefore, this pro- ject objective is to investigate the role of iris biomechanics in PACG through the evaluation of iridial biome- chanical properties and mechanics of AC and PB. In addition, we will investigate sex-dependent differences in iris biomechanics and their potential role in predisposing women to a higher risk of developing PACG. This project s specific aims (SA) are: SA1 - Investigate sex differences in the biomechanical properties of the iris using a hybrid in vivo/ex vivo approach in rabbits (K99 mentored phase). SA2 - Investigate sex differences in biomechanical properties of the human iris using in vivo and ex vivo (cadaver) analyses. SA3 - Investigate bio- mechanical conditions required to induce AC and PB, and their relation to sex and history of AC (R00). These studies will provide an improved understanding of the pathophysiology of PACG and a unique opportunity to combine engineering, basic science, and clinical research to address a significant public health issue. During the mentored phase, the applicant will learn multiple foundational techniques, including in vivo animal studies in rabbits, biomechanical analysis of active (muscular) tissue, histology, OCT imaging, and human sub- ject studies. In addition, he will significantly expand his professional training through various mechanisms. The skills and techniques learned during the mentored phase will build on the applicant s background in tissue bio- mechanics and allow him to pursue a successful and impactful independent academic career.