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

虹膜生物力学和性别差异在原发性闭角型青光眼中的作用

• 批准号: 10723800
• 负责人: Babak Naghizadeh Safa
• 金额: $ 11.2万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723800
• 关键词: Acute; Address; Adrenergic Agents; Affect; Age; Anatomy; Animal Model; Animals; Anterior; Anti-Cholinergics; Aqueous Humor; Basic Science; Biomechanics; Blindness; Cadaver; Cholinergic Agents; Clinical; Clinical Research; Clinical Trials; Computer Models; Data; Development; Dilator; Disparity; Elements; Engineering; Evaluation; Eye; Female; Functional disorder; Future; Glaucoma; Histology; Human; Hybrids; Image; Individual; Iris; Learning; Light; Link; Measures; Mechanics; Mentors; Modeling; Morbidity - disease rate; Muscle; Muscle Contraction; Mydriasis; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Physiologic Intraocular Pressure; Physiological; Play; Prevalence; Primary Angle Closure Glaucoma; Property; Protocols documentation; Public Health; Pupil light reflex; Race; Recording of previous events; Relaxation; Research Personnel; Risk; Risk Factors; Role; Sex Differences; Sphincter; Study Subject; Techniques; Testing; Tissues; Traction; Training; Validation; Woman; anterior chamber; biomechanical test; career; clinical risk; comparison control; constriction; high risk; human subject; improved; in vivo; lens induction; male; medically necessary care; pressure; prevent; risk stratification; sex; skills; therapeutic target

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.

初级角度闭合青光眼（PACG）是全世界不可逆失明的重要原因，影响c。 1700万人。 PACG在女性中更为普遍。不幸的是，这种不平等的根本原因 患病率未知。除性别以外的其他因素，例如前房间，种族和种族的解剖缺陷 年龄与PACG有关，解剖缺陷是接受的主要临床标准 评估PACG风险。但是，一些临床试验表明，这种解剖因素令人惊讶地差 PACG开发的预测因素，表明其他未指控因素参与PACG。 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 PACG的关键特征的瞳孔块（PB），虹膜与镜头之间的接触会诱导压力梯度 在前室和后腔之间。随后，PB导致流出途径的阻塞（即 角度闭合[AC]）通过虹膜的前变形，与眼内压的相关升高和 潜在的青光眼视力丧失。我们和其他人通过使用瞳孔反射（例如，触发）表明 从光线下），可以非侵入性评估虹膜的生物力学特性。有趣的是，在患者中 与对照组相比，PACG的历史是虹膜的僵硬。但是，虹膜生物力学在诱导AC中的作用 PACG是未知的。 我们的核心假设是，虹膜生物力学在发展基于PACG的基础上起着至关重要的，不受欢迎的作用 关于虹膜变形和虹膜生物力学特性之间的自然联系。因此，这个亲 JECT目标是通过评估虹膜生物组的评估来研究虹膜生物力学在PACG中的作用 AC和PB的机制和力学。此外，我们将研究与性别有关的差异 虹膜生物力学及其在使妇女越来越高的PACG风险中的潜在作用。 该项目的特定目的（SA）为：SA1-研究虹膜生物力学特性的性别差异 在兔子中使用杂种体内/离体方法（K99指导阶段）。 SA2-调查性别差异 使用体内和体内（尸体）分析的人虹膜生物力学特性。 SA3-研究生物 - 诱导AC和PB所需的机械条件及其与AC的性别和历史的关系（R00）。这些 研究将为PACG的病理生理学提供深入的了解，并提供独特的机会 结合工程，基础科学和临床研究，以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 兔子的研究，活性（肌肉）组织，组织学，OCT成像和人类亚的生物力学分析 JECT研究。此外，他将通过各种机制大大扩展他的专业培训。这 在指导阶段学到的技能和技术将建立在组织生物的申请人背景上 机械师，允许他从事成功而有影响力的独立学术职业。