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，衰老是发展青光眼的主要危险因素。 调节女性患青光眼的风险。 强调需要了解绝经组织的影响。 青光眼是多因素的，但眼内提升（IOP）仍然是IOP的主要危险因素 增加视神经头（ON）变形，导致视网膜神经节细胞的丧失和视力丧失 青光眼。 已知更年期调节整个人体组织的Stifff度会影响基因表达 视网膜。我们的假设是更年期威利 变形，从而增加了发展青光眼的风险，这些作用是由 巩膜中基因表达谱的改变。 该提案使用年龄和外科绝经列出了大鼠模型中的假设 目标1。 这项提案通过检查年轻人（3-4个月）和老年人（20-24）实现了这些目标 几个月）男性和女性长埃文斯大鼠。 更年期将通过生理学的卵巢切除术（老年人）进行。 用于评估肩call脚的力学，而相反的眼睛用于评估基因表达。 更年期会影响多个基因网络；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。 降低僵硬的刚度，支持我们的假设。 基因Express。 表达）对年龄，性别，更年期和青光眼之间的关联。 未来研究受年龄和更年期作为潜在治疗的途径。 治疗可以靶向机械性能或基因表达以降低发展 青光眼。