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

评估年龄、性别和更年期对巩膜生物力学和基因表达的影响

• 批准号: 10726826
• 负责人: Andrew J Feola
• 金额: $ 43.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726826
• 关键词: Address; Affect; Age; Age Years; Aging; Applications Grants; Biomechanics; Blindness; COL1A1 gene; Collagen; Connective Tissue; Contralateral; Custom; Data; Data Set; Devices; Disease; Elderly; Estrogens; Extracellular Matrix; Eye; Female; Future; Gene Expression; Genes; Glaucoma; Immune signaling; Individual; Inflammatory; Knowledge; Long-Evans Rats; Matrix Metalloproteinases; Measures; Mechanics; Mediating; Menopause; Modeling; Operative Surgical Procedures; Optic Disk; Ovariectomy; Pathway Analysis; Pathway interactions; Patients; Persons; Phase; Physiologic Intraocular Pressure; Physiological; Play; Population; Postmenopause; Predisposition; Premature Menopause; Premenopause; Prevalence; Property; Rattus; Retina; Retinal Ganglion Cells; Risk; Risk Factors; Role; Sclera; Signal Pathway; Signal Transduction; Tissue-Specific Gene Expression; Tissues; Visual impairment; Woman; Women' s Health; cohort; early experience; gene network; improved; insight; male; mechanical properties; modifiable risk; sex; surgical menopause; therapeutic target; transcriptome sequencing

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.

青光眼是全球不可逆失明的主要原因，预计将影响1.12亿人 到2040年青光眼的治疗方法有哪些？然而，有证据表明，更年期的年龄 调节女性患青光眼的风险。总体而言，女性占青光眼人群的59% 强调需要了解更年期对眼组织的影响。 青光眼是多因素的，但眼内压（IOP）升高仍然是一个主要的风险因素。IOP升高 增加视神经乳头（ONH）变形，导致视网膜神经节细胞丢失和视力丧失， 青光眼ONH的变形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硬度，并已知会影响基因表达， 视网膜在此，我们假设绝经会降低巩膜硬度，加重ONH 变形，从而增加患青光眼的风险，这些影响是由 改变了巩膜中的基因表达谱 这项建议解决了假设在大鼠模型中使用年龄和手术绝经跨越两个综合 目标。目的1测量巩膜的双相机械特性，目的2评估基因表达 的巩膜。本提案通过检查年轻人（3-4个月）和老年人（20-24岁）来实现这些目标 个月）雄性和雌性Long-Evans大鼠。年轻女性分为绝经前和绝经后两组。 更年期将发生卵巢切除术（年轻）的生理（老年人）。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， 更年期影响多个基因网络;因此，我们将使用RNAseq，一种无偏见的方法，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 降低巩膜硬度支持我们的假设我们还表明，年龄和卵巢切除术调节视网膜病变， 基因表达。该提议提供了功能（例如，巩膜力学）和力学（例如，基因 表达）对年龄、性别、绝经和青光眼之间的关联的洞察。该提案将建立 未来的应用研究受年龄和绝经影响的途径作为潜在的治疗。这些 治疗可以针对机械性能或基因表达，以降低对发育的敏感性。 青光眼