Impact of Menopause on the Aqueous Outflow Pathway

更年期对房水流出途径的影响

• 批准号: 10222707
• 负责人: Andrew J Feola
• 金额: $ 15.85万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222707
• 关键词: Address; Affect; Age; Animal Model; Animals; Atomic Force Microscopy; Biomechanics; Blindness; Blood Vessels; Connective Tissue; Contralateral; Data; Elderly; Estrogen Receptor beta; Estrogen Receptors; Estrogen Therapy; Estrogens; Event; Eye; Eye Development; Female; Genetic Polymorphism; Glaucoma; Goals; Individual; Life; Link; Literature; Measurement; Measures; Menopause; Metabolic Pathway; Modeling; Mutation; Norway; Ocular Hypertension; Open-Angle Glaucoma; Outcome Measure; Ovariectomy; Pathway interactions; Patients; Pelvic floor structure; Physiologic Intraocular Pressure; Physiological; Play; Population; Postmenopause; Premature Menopause; Premenopause; Process; Property; Proteins; Rattus; Rattus norvegicus; Relative Risks; Resistance; Risk; Risk Factors; Role; Structure; Surgical Models; Tissues; Trabecular meshwork structure; Woman; Women' s Health; age effect; aged; aqueous; base; clinical translation; cohort; experimental study; high intraocular pressure; hormone therapy; insight; male; men; middle age; normotensive; novel therapeutics; prevent; protein expression; sex; tonometry

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.

项目摘要/摘要 青光眼是不可逆转失明的主要原因，预计将影响全球1.12亿人 到2040年。女性占青光眼人口的59%，强调了了解是否有 青光眼的性别相关危险因素。例如，更年期早会增加患青光眼的风险。 女性雌激素受体基因多态性与高眼压(一种重要的致病风险)相关 青光眼的因素)。更年期会导致眼压升高1-3毫米汞柱，而 含有雌激素的激素疗法可降低眼压。这些数据表明，绝经年龄、更年期 雌激素水平影响青光眼风险或眼压，但机制尚不清楚(S)。 眼压受多种因素影响，但房水流出阻力是主要的决定因素。 由小梁网络(TM)功能控制。流出阻力是分段的，有高流区和低流区， 节段性血流与TM刚性相关。值得注意的是，更年期和雌激素水平会影响 这可能是雌激素水平改变影响眼压的一种机制。这些变化在 节段性血流可能与蛋白质表达改变有关，因为更年期会改变已知的蛋白质水平 影响水的流出阻力。因此，可以假设更年期通过增加眼压来增加眼压。 通过在高流动区和低流动区使TM变硬来增加水的流出阻力，从而增加 女性患青光眼的风险。这一建议解决了在一个动物模型中的假设 通过测量绝经期眼压和房水流出阻力(目标1)，以及使用原子技术测量局部TM硬度 力显微镜(目标2)。 该提案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 青年(3-4个月)和中年(9-10个月)女性绝经、卵巢切除(OVX) 棕色挪威大鼠和生理性更年期老年雌性大鼠(18-19月龄)。实验B将 确定局部雌激素疗法是否减轻更年期的影响，并调查这种疗法是否影响 老年雄性大鼠(18-19月龄)的眼压、流出阻力和TM硬度。在所有动物中，眼压将是 使用反弹眼压测量仪测量8周，然后测量流出阻力(通过iFusion) 一只眼的局部TM僵硬(通过原子力显微镜)。对侧眼将被用来评估： 沿着流出途径的雌激素水平或结构和成分。初步数据支持这一假设， 显示OVX后眼压和房水流出阻力增加。这项提议将建立在这些基础上 数据，并期望证明更年期增加TM僵硬和局部雌激素治疗 阻止这些更改。这些发现将提供对这种联系的功能性和机械性的洞察 在更年期和青光眼之间，以及局部雌激素治疗作为青光眼治疗的好处。