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

原发性闭角型青光眼(PACG)是世界范围内导致不可逆性失明的重要原因。 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 流行率尚不清楚。性别以外的因素，如前房解剖缺陷、种族和 年龄与PACG有关，解剖缺陷是公认的主要临床标准，用于 评估PACG风险。然而，几项临床试验表明，这些解剖学因素出人意料地差。 PACG发展的预测因素，表明其他不明因素参与了PACG。 PACG的病理生理机制与虹膜生物力学密切相关。具体而言，在 瞳孔阻滞(PB)是PACG的一个重要特征，虹膜与晶状体之间的接触会引起压力梯度。 前房和后房之间。随后，PB导致流出通道闭塞(即， 房角闭合[AC])，由虹膜前变形引起，伴随眼压升高和 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) 光)，可以非侵入性地评估虹膜的生物力学特性。有趣的是，在患有 作为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 而PACG是未知的。 我们的中心假设是，虹膜生物力学在发展PACG中扮演着关键的、未被认识的角色。 虹膜变形与虹膜生物力学特性之间的天然联系。因此，这位亲王- 目的通过对虹膜生物群的评价，探讨虹膜生物力学在PACG中的作用。 AC和PB的力学性能和力学性能。此外，我们还将研究性别相关的差异 虹膜生物力学及其在提高女性患PACG风险中的潜在作用。 S项目的具体目的是：研究虹膜生物力学特性的性别差异 采用体内/体外混合方法(K99指导阶段)。SA2-调查性别差异 人体虹膜生物力学特性的体内和体外(身体)分析。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，并提供一个独特的机会 将工程学、基础科学和临床研究结合起来，解决一个重大的公共卫生问题。 在指导阶段，申请者将学习多种基础技术，包括活体动物 兔的研究，活动(肌肉)组织的生物力学分析，组织学，OCT成像，和人类亚 主题研究。此外，他还将通过各种机制大幅扩大他的专业培训。这个 在指导阶段学到的技能和技巧将建立在申请人S组织生物学背景的基础上。 并允许他追求成功和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.