Assessing the Impact of Age, Sex, and Menopause on Scleral Biomechanics and Gene Expression

青光眼是全球不可逆转失明的主要原因，预计将影响1.12亿人 到2040年。衰老是发展成青光眼的主要危险因素。然而，有证据表明，更年期年龄 调节女性患青光眼的风险。总体而言，女性占青光眼人口的59% 强调有必要了解更年期对眼组织的影响。 青光眼是多因素的，但眼压升高仍然是一个主要的危险因素。高眼压 视神经头(ONH)变形增加，导致视网膜神经节细胞丢失和视力丧失 青光眼。ONH变形的程度与眼压和眼生物力学特性有关。年龄和 更年期调节全身组织的僵硬，并已知影响基因表达 视网膜。在这里，我们的假设是绝经会降低巩膜僵硬，加剧ONH 变形因此增加了患青光眼的风险，这些影响是通过 巩膜中基因表达谱的改变。 这一建议解决了大鼠模型中的假设，该模型使用年龄和手术绝经 目标。目的1测量巩膜的双相力学性能，目的2评估基因表达 在巩膜上。这项建议通过检查年轻人(3-4个月)和老年人(20-24岁)来实现这些目标 月)雄性和雌性Long-Evans大鼠。年轻女性被分为绝经前和绝经后两组。 更年期将通过生理上(老年人)的卵巢切除(年轻的)发生。在我们的综合目标中，一只眼睛 用于评估巩膜力学，而对侧眼用于评估基因表达。年龄、性别和 更年期影响多个基因网络；因此，我们将使用RNAseq，一种公正的方法，来检查 与细胞外基质重塑相关的基因表达。我们的初步数据显示，卵巢切除术 减少巩膜僵硬，支持我们的假设。我们还发现年龄和卵巢切除对视网膜有调节作用。 基因表达。该建议提供了功能性(例如，巩膜力学)和机械性(例如，基因 洞察年龄、性别、更年期和青光眼之间的联系。这项提案将设立 未来应用于研究受年龄和更年期影响的通路，作为潜在的治疗方法。这些 治疗可以针对机械性能或基因表达来降低发展的易感性 青光眼。

Glaucoma is the leading cause of irreversible blindness worldwide and is projected to affect 112 million people by 2040. Aging is a major risk factor for developing glaucoma. Yet, evidence suggests that the age of menopause modulates a woman’s risk of developing glaucoma. Overall, women represent 59% of the glaucoma population highlighting the need to understand the impact of menopause on ocular tissues. Glaucoma is multifactorial but elevated intraocular pressure (IOP) remains a major risk factor. Elevated IOP increases optic nerve head (ONH) deformation contributing to the loss of retinal ganglion cells and vision loss in glaucoma. The extent of ONH deformation is related to IOP and ocular biomechanical properties. Age and menopause modulate the stiffness of tissues throughout the body and are known to affect gene expression in the retina. Here, our hypothesis is that menopause will decrease scleral stiffness, exacerbating ONH deformation thus increasing the risk of developing glaucoma and that these effects are mediated by altered gene expression profiles in the sclera. This proposal addresses the hypothesis in a rat model using age and surgical menopause across two integrated Aims. Aim 1 measures the biphasic mechanical properties of the scleral and Aim 2 assesses gene expression of the sclera. This proposal achieves these Aims by examining young (3-4 months) and older adult (20-24 months) male and female Long-Evans rats. Young females are divided into pre- and post-menopausal groups. Menopause will occur by ovariectomy (young) of physiologically (older adults). In our integrated Aims, one eye is used to assess scleral mechanics while the opposite eye is used to assess gene expression. Age, sex, and menopause affect multiple gene networks; therefore, we will use RNAseq, an unbiased approach, to examine gene expression associated with extracellular matrix remodeling. Our preliminary data show that ovariectomy decreases scleral stiffness, supporting our hypothesis. We also show that age and ovariectomy modulate retinal gene expression. This proposal provides functional (e.g., scleral mechanics) and mechanistic (e.g., gene expression) insight into the association between age, sex, menopause, and glaucoma. This proposal will set up future applications to investigate pathways affected by age and menopause as potential treatments. These treatments can target mechanical properties or gene expression to decrease the susceptibility to developing glaucoma.