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Effects of estrogen on trabecular meshwork regulation of intraocular pressure

雌激素对小梁网眼压调节的影响

基本信息

批准号：
10223214
负责人：
Hannah Abigail Youngblood
金额：
$ 4.04万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223214
关键词：
Affect Age Age at Menarche Anterior Aqueous Humor Aromatase Autopsy Bilateral oophorectomy Bioinformatics Biological Biological Assay Blindness CAV1 gene CAV2 gene CYP1B1 gene Cattle Cell Death Cell physiology Cells Cellular Morphology Contracts Cornea Development Dexamethasone Disease ESR1 gene Estradiol Estrogen Receptor alpha Estrogens Eye Female Fertility Gene Expression Profile Genes Genetic Transcription Glaucoma Goals Growth Health High Prevalence Hormone replacement therapy Hormone use Human Human Activities Impairment Individual Iris Knock-out Knockout Mice Measures Menopause Monitor Morphology Mus Nerve Degeneration Optic Nerve Optical Coherence Tomography Oral Contraceptives Ovariectomy Pathogenesis Pathway interactions Patients Phagocytes Phagocytosis Physiologic Intraocular Pressure Play Postmenopause Pregnancy Premenopause Primary Open Angle Glaucoma Regulation Research Resistance Retina Retinal Ganglion Cells Risk Risk Factors Role Signal Transduction Testing Thinness Trabecular meshwork structure Transcriptional Regulation Transforming Growth Factor Beta 2 Vision Visual Fields Wild Type Mouse base cell type epidemiology study extracellular genome wide association study improved innovation male modifiable risk mouse model new therapeutic target novel pressure protective effect receptor response therapeutic target transcriptome sequencing treatment response

项目摘要

PROJECT SUMMARY The goal of this project is to characterize the effects of estrogen and its receptor - estrogen receptor 1 (ESR1) - on aqueous humor outflow, intraocular pressure, and risk for glaucoma development. Primary open-angle glaucoma (POAG), as the most common subtype of glaucoma, is characterized by retinal ganglion cell death, optic nerve degeneration, and progressive visual field loss without an identifiable cause. Elevated intraocular pressure (IOP) is the primary and only modifiable risk factor for POAG development. This pressure is regulated by the trabecular meshwork (TM) which modulates aqueous humor (AH) outflow. Previously, genome-wide association studies identified >122 IOP-associated genes. Our integrated bioinformatics analysis revealed that ESR1, also known as estrogen receptor α, was at the center of a functional network of these IOP-associated genes, suggesting that it may play a role in IOP regulation. Several epidemiological studies have suggested that low estrogen levels may contribute to glaucoma risk due to a higher prevalence of POAG in males than females and a higher prevalence in post-menopausal females than pre-menopausal females or post-menopausal females undergoing hormone replacement therapy. Inversely, pregnancy, a high estrogen state, has been associated with lower IOP. In addition, it has been well-established that estrogen is protective for several ocular cell types, including retinal and corneal cells. However, the impact of estrogen on the TM has yet to be explored. Therefore, in this proposal, we hypothesize that moderate estrogen levels reduce IOP and POAG risk by promoting proper TM function through ESR1 transcriptional regulation of IOP and POAG related genes. We will test this hypothesis with the following aims. In Aim 1, in order to assess the effects of estrogen signaling on IOP and ocular health, we will measure IOP and conduct retinal optical coherence tomography (OCT) on male and female Esr1-/- mice and wild type female mice undergoing a bilateral oophorectomy. In Aim 2 we will determine the effects of estradiol, the active form of estrogen, on the transcriptional profile, morphology, and function of primary human TM cells using RNA-Seq and growth, contraction, and phagocytic assays. Successful completion of this project will improve our current understanding of the role of the TM in POAG pathogenesis, confirm low estrogen levels as a novel risk factor for high tension POAG, and identify novel therapeutic targets for this blinding illness.

项目摘要本项目的目标是描述雌激素及其受体-雌激素受体1（ESR 1）的作用。 - 对房水流出、眼内压和青光眼发展风险的影响。原发性开角型青光眼（POAG）作为青光眼最常见的亚型，其特征在于视网膜神经节细胞死亡，视神经变性和进行性视野丧失而没有可识别的原因。升高的眼内眼压（IOP）是POAG发展的主要和唯一可改变的危险因素。该压力由小梁网（TM）调节，小梁网（TM）调节房水（AH）流出。在此之前，全基因组关联研究确定了>122个IOP相关基因。我们的综合生物信息学分析显示，ESR 1，也称为雌激素受体α，是一个功能网络的中心，这些IOP相关基因，表明它可能在IOP调节中发挥作用。一些流行病学研究表明，低雌激素水平可能会导致青光眼的风险，由于更高的患病率，男性POAG的患病率高于女性，绝经后女性的患病率高于绝经前接受激素替代疗法的女性或绝经后女性。怀孕，怀孕，高雌激素状态与低IOP相关。此外，已经确定雌激素是保护几种眼部细胞类型，包括视网膜和角膜细胞。然而，雌激素的影响还有待探索。因此，在这个提议中，我们假设适度的雌激素水平通过ESR 1对IOP的转录调节促进适当的TM功能，降低IOP和POAG风险 POAG相关基因我们将以下列目标来检验这一假设。在目标1中，为了评估为了研究雌激素信号对IOP和眼部健康的影响，我们将测量IOP并进行视网膜光学检查。对雄性和雌性Esr 1-/-小鼠和野生型雌性小鼠进行相干断层扫描（OCT），双侧卵巢切除术在目标2中，我们将确定雌二醇（雌激素的活性形式）对使用RNA-Seq和生长的原代人TM细胞的转录谱、形态和功能，收缩和吞噬测定。该项目的成功完成将改善我们目前的了解TM在POAG发病机制中的作用，证实低雌激素水平是一种新的危险因素高张力POAG，并确定新的治疗目标，这种致盲性疾病。