The Effect of Estrogen Deficiencies on Vision Loss in Glaucoma

雌激素缺乏对青光眼视力丧失的影响

• 批准号: 10382223
• 负责人: Andrew J Feola
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382223
• 关键词: Affect; Age; Anatomy; Animals; Attention; Attenuated; Axon; Biomechanics; Blindness; Brain; Cartilage; Cell Survival; Cell physiology; Cervix Uteri; Clinical; Clinical Trials; Complement; Connective Tissue; Contrast Sensitivity; Data; Development; Disease; Electroretinography; Environment; Estrogen Metabolism; Estrogen Receptors; Estrogen Therapy; Estrogens; Etiology; Experimental Models; Exposure to; Eye; Female; Future; Gelatinase A; Gelatinase B; Gender; General Population; Genetic Polymorphism; Glaucoma; Goals; Health; Image; Individual; Inflammation Mediators; Inflammatory; Interleukin-6; Lead; Link; Matrix Metalloproteinases; Measures; Mechanics; Menopause; Mentorship; Metabolic Pathway; Modeling; Monitor; Mutation; Norway; Ocular Hypertension; Optic Disk; Optical Coherence Tomography; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Persons; Physiologic Intraocular Pressure; Play; Population; Postmenopause; Predisposition; Premature Menopause; Premenopause; Property; Protease Inhibitor; Rattus; Reporting; Research; Research Personnel; Retinal Ganglion Cells; Risk; Risk Factors; Role; Sclera; System; TNF gene; Testing; Therapeutic; Time; Tissues; Training; Vagina; Veterans; Vision; Visual Acuity; Visual Fields; Visual impairment; Woman; World Health Organization; aged; biomechanical test; bone; conventional therapy; inflammatory marker; inhibitor therapy; insight; interdisciplinary approach; juvenile animal; male; mechanical properties; military veteran; novel therapeutics; post-doctoral training; preservation; prevent; rehabilitation research; research and development; tonometry; tool; visual dysfunction; visual information; visual neuroscience

Glaucoma is the largest cause of irreversible blindness in the world and is characterized by the loss of retinal ganglion cells (RGCs), which transmit visual information from the eye to the brain. While the exact cause of glaucoma is unknown, recent evidence has shown that early menopause in women is linked with developing glaucoma. Further, mutations in estrogen receptors and polymorphisms in the estrogen metabolic pathway are linked with glaucoma in both genders. However, since the number of woman veterans has nearly doubled in the last ten years, the VA recently formed the Women’s Veterans Health Research Network (WVHRN) to help focus attention on research and treatments for this increasing population in the veteran population. These data highlight that estrogen plays a vital role in the development of glaucoma and is an important issue in the VA; however, the mechanism(s) underlying estrogen’s effects are unknown. We hypothesize that an estrogen deficiency contributes to the etiology of glaucoma by altering ocular biomechanics, increasing an individual’s risk for developing glaucoma. In this study, we will investigate the link between estrogen and glaucoma through three Specific Aims. In our first specific aim, we will measure the impact of menopause on ocular compliance and scleral mechanical properties in pre- and post-menopausal young (3-4 month) and aged (9-10 month) female rats. This will allow us to assess how estrogen deficiencies alter the biomechanical properties of the eye, which may impact RGC survival. In our second specific aim, we will evaluate the effect of early and late menopause in rats with experimental glaucoma/ocular hypertension. Specifically, over 12 weeks, we will investigate functional visual impairment (e.g. visual acuity and contrast sensitivity), RGC function and anatomical changes in the eye due to experimental glaucoma. Further, we will investigate the potential therapeutic benefits of estrogen in female and male rats with experimental glaucoma. This will allow us to determine whether estrogen therapy can preserve visual function after inducing experimental glaucoma. Our third specific aim will examine the impact of menopause on inflammatory markers and protease expression in the eye. We will also assess if the inhibition of inflammatory and protease expression prevents changes in ocular compliance associated with menopause. This investigates the potential mechanism(s) that an estrogen deficiency induces changes in ocular biomechanical properties. Our preliminary data support this overall hypothesis. We expect to build off these strong data and find that menopause will differentially influence the biomechanical properties of the eye, with young animals having a larger impact from an estrogen deficiency. We also anticipate finding that post-menopausal rats have more severe visual impairment compared to pre-menopausal rats and that estrogen therapy will preserve visual function in post-menopausal females and aged male with experimental glaucoma. Lastly, we believe that menopause will increase inflammatory markers and protease expression and that inhibiting these changes after menopause will preserve ocular biomechanical properties. These data will provide the first clear picture of how estrogen modulates the risk of developing glaucoma. If we are successful in our aims, these finding will motivate the development of estrogen as a novel therapeutic treatment for glaucoma. Overall, this study will provide information on how estrogen is linked to glaucoma and motive us to develop future studies that will investigate estrogen as a novel therapeutic treatment for glaucoma of female and male veterans in the VA clinical population. This meets the Rehabilitation Research and Development goal of preventing and treating vision loss. This CDA2 will aid in the ongoing training of the postdoctoral candidate to become an independent and successful investigator in the fields of visual neuroscience, biomechanics and glaucoma within the VA environment.

青光眼是世界上导致不可逆性失明的最大原因，其特征是视网膜丧失 神经节细胞(RGC)，将视觉信息从眼睛传递到大脑。而真正的原因 青光眼是未知的，最近的证据表明，女性更年期提前与发育有关。 青光眼。此外，雌激素受体的突变和雌激素代谢途径的多态是 无论男女，都与青光眼有关。然而，由于女性退伍军人的数量在#年几乎翻了一番。 在过去的十年里，退伍军人管理局最近成立了女性退伍军人健康研究网络(WVHRN)来帮助 将注意力集中在研究和治疗退伍军人群体中不断增长的人口上。这些数据 强调雌激素在青光眼的发展中起着至关重要的作用，是退伍军人事务部的一个重要问题； 然而，雌激素作用的潜在机制(S)尚不清楚。我们假设一种雌激素 青光眼的发病机制主要是通过改变眼部生物力学、增加眼球运动功能而引起的。 个人患青光眼的风险。在这项研究中，我们将研究雌激素和 青光眼通过三个特定的目标。在我们的第一个具体目标中，我们将测量更年期对 青年绝经前后(3-4个月)和 老龄(9-10月龄)雌性大鼠。这将使我们能够评估雌激素缺乏如何改变生物力学 眼睛的特性，这可能会影响RGC的生存。在我们的第二个具体目标中，我们将评估效果 对实验性青光眼/高眼压大鼠绝经早期和晚期的影响。具体地说，超过12个 周，我们将调查功能性视力损害(例如视力和对比敏感度)，RGC 实验性青光眼引起的眼功能和解剖变化。此外，我们将调查 雌激素对实验性青光眼雌雄大鼠的潜在疗效。这将允许 以确定雌激素治疗是否能在诱发实验性青光眼后保留视功能。 我们的第三个具体目标是检查更年期对炎症标志物和蛋白水解酶的影响。 眼睛里的表情。我们还将评估抑制炎症和蛋白水解酶表达是否会阻止 与更年期相关的眼部顺应性改变。这就考察了潜在的机制(S) 雌激素缺乏会导致眼部生物力学特性的改变。我们的初步数据支持这一点 总体假设。我们希望建立在这些强有力的数据基础上，并发现更年期会有不同 影响眼睛的生物力学特性，幼年动物受到雌激素的影响更大 缺乏症。我们还预计会发现绝经后的大鼠有更严重的视力障碍 与绝经前大鼠相比，雌激素治疗将保留绝经后大鼠的视觉功能 女性和老年男性实验性青光眼。最后，我们认为更年期将会增加 炎症标记物和蛋白酶的表达以及在绝经后抑制这些变化将 保存眼睛的生物力学特性。这些数据将提供第一张清晰的图片，说明雌激素是如何 调节患青光眼的风险。如果我们的目标是成功的，这些发现将激励 雌激素作为青光眼新疗法的研究进展。总体而言，这项研究将提供 关于雌激素如何与青光眼有关的信息，并促使我们发展未来的研究，将调查 雌激素作为治疗退伍军人青光眼的新方法 人口。这符合防治视力的康复研究和发展目标 损失。这一CDA2将有助于博士后候选人成为独立和 在视觉神经科学、生物力学和退伍军人事务部青光眼领域的成功研究者 环境。