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.

原发性闭角型青光眼（PACG）是世界范围内不可逆性失明的重要原因，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是， 患病率未知。性别以外的因素，如前房的解剖缺陷，种族， 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，几项临床试验表明，这样的解剖因素是惊人的差 PACG发展的预测因素，表明PACG中其他未考虑的因素的参与。 PACG的病理生理机制与虹膜的生物力学密切相关。具体到 瞳孔阻滞（PB）是PACG的一个关键特征，虹膜和透镜之间的接触引起压力梯度 在前房和后房之间随后，PB导致流出路径的阻塞（即， 虹膜前部变形导致房角关闭[AC]），并伴有相关的眼内压升高， 潜在的昏迷性视力丧失我们和其他人已经表明，通过使用瞳孔反射（例如，触发 通过光），可以非侵入性地评估虹膜的生物力学特性。有趣的是， PACG病史，虹膜比对照组更僵硬。然而，虹膜生物力学在诱发AC中的作用 PACG未知。 我们的中心假设是，虹膜生物力学在发展PACG中起着至关重要的，未被重视的作用， 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- 目的通过对虹膜生物力学的评价，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，我们还将研究性别依赖的差异， 虹膜生物力学及其在诱发女性发生PACG的高风险中的潜在作用。 本项目的具体目标（SA）是：SA1-研究虹膜生物力学特性的性别差异 在兔中使用混合体内/离体方法（K99指导阶段）。SA2-调查 使用体内和离体（尸体）分析的人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 研究将提供一个更好的了解PACG的病理生理学和一个独特的机会， 联合收割机工程，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 在兔子中的研究，活性（肌肉）组织的生物力学分析，组织学，OCT成像，和人类亚 专题研究。此外，他将通过各种机制大大扩大他的专业培训。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学背景上， 机械，让他追求一个成功的和有影响力的独立学术生涯。