The Effect of Estrogen Deficiencies on Vision Loss in Glaucoma

青光眼是世界上最大的不可逆性失明的原因，其特征在于视网膜色素变性的丧失。 神经节细胞（RGC），将视觉信息从眼睛传递到大脑。虽然确切原因是 青光眼是未知的，最近的证据表明，妇女更年期提前与发展 青光眼此外，雌激素受体的突变和雌激素代谢途径中的多态性也是影响雌激素代谢的重要因素。 与青光眼有关。然而，由于退伍妇女人数在1999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妇女退伍军人健康研究网络（WVHRN），以帮助 把注意力集中在研究和治疗这一不断增加的退伍军人群体。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VA中的一个重要问题; 然而，雌激素的作用机制尚不清楚。我们假设雌激素 缺乏通过改变眼生物力学，增加和降低眼压， 患青光眼的风险。在这项研究中，我们将调查雌激素和 青光眼通过三个具体目标。在我们的第一个具体目标中，我们将测量更年期对 绝经前和绝经后年轻人（3-4个月）的眼顺应性和巩膜机械特性， 年龄（9-10个月）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 实验性青光眼/高眼压大鼠绝经早期和晚期的变化。具体来说，超过12 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学变化。此外，我们将调查 雌激素对实验性青光眼雌性和雄性大鼠的潜在治疗益处。这将允许 我们要确定雌激素治疗是否能在诱导实验性青光眼后保留视功能。 我们的第三个具体目标是研究绝经对炎症标志物和蛋白酶的影响。 眼睛里的表情。我们还将评估炎症和蛋白酶表达的抑制是否能阻止 与绝经相关的眼顺应性变化。本研究探讨了 雌激素缺乏引起眼生物力学性质的变化。我们的初步数据支持这一点 整体假设。我们希望建立这些强有力的数据，并发现更年期将差异 影响眼睛的生物力学特性，年轻的动物受到雌激素的影响更大 缺陷我们还预计发现，绝经后的大鼠有更严重的视力障碍， 与绝经前大鼠相比，雌激素治疗可以保护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，我们认为更年期会增加 炎症标志物和蛋白酶表达，绝经后抑制这些变化将 保持眼部生物力学特性。这些数据将提供第一个明确的图片如何雌激素 调节患青光眼的风险。如果我们成功地实现了我们的目标，这些发现将激励我们的工作。 发展雌激素作为青光眼的一种新的治疗方法。总的来说，这项研究将提供 关于雌激素与青光眼之间关系的信息，促使我们开展未来的研究， 雌激素作为一种新的治疗青光眼的女性和男性退伍军人在退伍军人临床 人口这符合康复研究和发展的目标，预防和治疗视力 损失该CDA 2将有助于博士后候选人的持续培训，使其成为一个独立的， 在视觉神经科学、生物力学和青光眼领域的成功研究者 环境

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.