Effects of estrogen on trabecular meshwork regulation of intraocular pressure

项目总结 本项目的目标是研究雌激素及其受体-雌激素受体1(ESR1)的作用。 -房水流出、眼压和青光眼发展风险。一次开度角 青光眼作为青光眼最常见的亚型，以视网膜神经节细胞死亡为特征， 视神经变性和进行性视野丧失，原因不明。高位眼内 压力(IOP)是POAG发生的主要且唯一可改变的危险因素。这种压力是 由小梁网络(TM)调节，它调节房水(AH)流出。此前， 全基因组关联研究确定了122个与眼压相关的基因。我们的综合生物信息学 分析表明，ESR1，也被称为雌激素受体α，处于一个功能网络的中心 这些与眼压相关的基因，提示其可能在眼压调节中发挥作用。几种流行病学 研究表明，由于青光眼患病率较高，低雌激素水平可能会导致青光眼风险增加。 男性的POAG患病率高于女性，绝经后女性的患病率高于绝经前 接受激素替代治疗的女性或绝经后女性。相反，怀孕，高潮 雌激素状态，一直与低眼压有关。此外，众所周知，雌激素是 保护多种眼细胞类型，包括视网膜和角膜细胞。然而，雌激素的影响 关于TM的问题还有待探索。因此，在这项提案中，我们假设适度的雌激素水平 通过ESR1对眼压的转录调控促进适当的TM功能，从而降低眼压和POAG风险 和POAG相关基因。我们将通过以下目标来检验这一假设。在目标1中，为了评估 雌激素信号对眼压和眼健康的影响，我们将测量眼压并进行视网膜光学检查 雄性和雌性ESR1-/-小鼠和野生型雌性小鼠的相干断层扫描 双侧卵巢切除术。在目标2中，我们将确定雌激素的活性形式雌二醇对 利用RNA-Seq和Growth对原代人TM细胞转录图谱、形态和功能的研究 收缩和吞噬试验。这个项目的成功完成将改善我们目前的状况 了解TM在POAG发病机制中的作用，确认低雌激素水平是一个新的危险因素 治疗高血压性POAG，并为这种致盲疾病确定新的治疗靶点。

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.