Impact of Menopause on the Aqueous Outflow Pathway

项目总结/摘要 青光眼是导致不可逆失明的主要原因，预计全球有1.12亿人患有青光眼 到2040年女性占青光眼人群的59%，强调需要了解是否有 青光眼的危险因素例如，过早绝经会增加患青光眼的风险。 女性雌激素受体多态性与高眼压（一种重要的致病风险）相关 青光眼的因素）。此外，绝经会导致眼内压（IOP）升高1-3 mmHg， 含有雌激素的激素疗法降低IOP。这些数据表明，绝经年龄， 雌激素水平影响青光眼风险或IOP，但其机制尚不清楚。 IOP受许多因素影响，但房水流出阻力是关键决定因素，其主要是 由小梁网（TM）功能控制。流出阻力是分段的，具有高流量区和低流量区， 节段性血流与TM刚度相关。值得注意的是，更年期和雌激素水平会影响 许多组织，提示雌激素水平改变影响IOP的可能机制。的这些变化 节段性血流可能与蛋白质表达的改变有关，因为绝经改变了已知的蛋白质水平， 影响水流出阻力。因此，假设绝经期通过增加IOP升高， 通过在高流量和低流量区域硬化TM，从而增加了水流出阻力， 女性患青光眼的风险。这一提议解决了动物模型中的假设， 通过测量IOP和房水流出阻力（目标1）以及使用Atomic 力显微镜（目标2）。 该提议通过几种方法实现了这些目标：实验A采用了一个完善的模型 绝经后，卵巢切除术（OVX），在年轻（年龄3-4个月）和中年（年龄9-10个月）女性 Brown Norway大鼠和老年雌性大鼠（年龄18-19个月）的生理绝经期。实验B将 确定局部雌激素治疗是否减轻更年期的影响，并调查这种治疗是否影响 老年雄性大鼠（年龄18-19个月）的IOP、流出阻力和TM刚度。在所有动物中，IOP将为 使用回弹眼压计测量8周，然后测量流出阻力（通过iPerfusion） 和局部TM硬度（通过原子力显微镜）。将使用外侧眼评估： 雌激素水平或结构和组成沿着流出途径。初步数据支持这一假设， 表明OVX后IOP和房水流出阻力增加。这项建议将建立在这些 数据，并期望证明绝经增加TM刚度和局部雌激素治疗， 阻止这些变化。这些发现将提供功能和机制的洞察协会 绝经和青光眼之间的关系，以及局部雌激素治疗作为青光眼治疗的益处。

Project Summary/Abstract Glaucoma is the leading cause of irreversible blindness and is projected to affect 112 million people worldwide by 2040. Women represent 59% of the glaucoma population, highlighting the need to understand if there are sex-specific risk factors for glaucoma. For example, early menopause increases the risk of developing glaucoma. Estrogen receptor polymorphisms in women are associated with ocular hypertension (an important causal risk factor for glaucoma). Moreover, menopause causes a 1-3 mmHg increase in intraocular pressure (IOP), while hormone therapy containing estrogen reduces IOP. These data suggest that the age of menopause, menopause and estrogen levels influence glaucoma risk or IOP, but the mechanism(s) is unknown. IOP is affected by many factors, but aqueous outflow resistance is the key determinant, which is primarily controlled by trabecular meshwork (TM) function. Outflow resistance is segmental with high and low flow regions, and segmental flow correlates with TM stiffness. Notably, menopause and estrogen levels affect the stiffness of many tissues, suggesting a possible mechanism by which altered estrogen levels affect IOP. These changes in segmental flow may be related to altered protein expression since menopause alters protein levels known to influence aqueous outflow resistance. Thus, it is hypothesized that menopause increases IOP by increasing aqueous outflow resistance through stiffening the TM in high and low flow regions, thus increasing a woman’s risk of developing glaucoma. This proposal addresses the hypothesis in an animal model of menopause by measuring IOP and aqueous outflow resistance (Aim 1), and regional TM stiffness using Atomic Force Microscopy (Aim 2). This proposal achieves these aims using several approaches: Experiment A employs a well-established model of menopause, ovariectomy (OVX), in young (age 3-4 months) and middle-aged (age 9-10 months) female Brown Norway rats, and physiological menopause in elderly female rats (age 18-19 months). Experiment B will determine if topical estrogen therapy mitigates the effects of menopause, and investigates if this therapy affects IOP, outflow resistance, and TM stiffness in elderly male rats (age 18-19 months). In all animals, IOP will be measured using rebound tonometry for 8 weeks, followed by measurement of outflow resistance (via iPerfusion) and regional TM stiffness (via atomic force microscopy) in one eye. Contralateral eyes will be used to assess: estrogen levels or structure and composition along the outflow pathway. Preliminary data support this hypothesis, showing that IOP and aqueous outflow resistance are increased after OVX. This proposal will build on these data and expects to demonstrate that menopause increases TM stiffness and that topical estrogen therapy prevents these changes. These findings will provide functional and mechanistic insight into the association between menopause and glaucoma, and the benefits of topical estrogen therapy as a treatment for glaucoma.