Estrogen and its Receptor in Intraocular Pressure Regulation

摘要 本申请的目的是确定雌激素及其受体-雌激素受体1（ESR 1）的作用。 和G蛋白偶联雌激素受体（GPER 1）-通过调节眼内压（IOP） 小梁网（TM）和Schlemm管（SC）内皮细胞。IOP是主要的，也是唯一可修改的 原发性开角型青光眼（POAG）患者的危险因素。TM和SC调制 大部分的房水流出阻力在传统的途径。尽管有大量的研究 TM/SC流出动力学的进展，有限的治疗靶点可用于调节常规的 外流有必要确定新的靶点，以更有效地降低青光眼患者的IOP， 进行性视野丧失最近的几项全基因组关联研究已经确定了>150 IOP- 相关的基因组基因座，数量太多，无法进行功能追踪。我们全面的生物信息学 对这些IOP相关基因座的分析表明ESR 1相关基因网络的富集 在这些IOP基因中。与月经初潮、绝经和卵巢切除术相关的因素已被 与POAG有关。雌激素序列变异之间的遗传关联已经被确定 受体通路基因和POAG。雌激素和ESR 1相关通路包括芳香化酶可能影响 眼房水流出设施和调节IOP水平。眼房水中雌二醇的存在， TM/SC区域的ESR 1蛋白进一步支持雌激素和ESR 1相关通路的潜在作用 眼压调节。根据我们对小鼠模型的IOP水平升高的初步数据， 以及它们与Nos 3的相互作用，我们假设雌激素信号的激活 通过ESR 1和GPER 1调节细胞外基质的周转，降低IOP和POAG的风险。 TM和一氧化氮信号在SC。我们建议，以确定在体内的影响损失的雌激素信号 通过Gper 1（Aim 1）或Esr 1（Aim 2）在小鼠眼中使用组织特异性敲除小鼠，并确定 使用体外原代细胞培养模型研究Gper 1和Esr 1介导的IOP调节的潜在机制 （目标3）。该项目的成功完成将有助于揭示雌激素信号在水环境中的关键作用。 外流途径，并确定新的治疗靶点，以更有效地降低IOP， 疾病

Abstract The goal of this application is to determine the role of estrogen and its receptors - estrogen receptor 1 (ESR1) and G protein coupled estrogen receptor (GPER1) – in regulating intraocular pressure (IOP) through trabecular meshwork (TM) and Schlemm's canal (SC) endothelial cells. IOP is the primary and only modifiable risk factor for patients affected with primary open-angle glaucoma (POAG) in the clinic. TM and SC modulate majority of aqueous humor outflow resistance in the conventional pathway. Despite the significant research progress in TM/SC outflow dynamics, limited therapeutic targets are available for modulating the conventional outflow. It is necessary to identify novel targets to lower IOP more efficiently in glaucoma patients with progressive visual field loss. Several recent genome-wide association studies have identified >150 IOP- associated genomic loci, which is too many to follow up functionally. Our comprehensive bioinformatics analyses of these IOP-associated genomic loci indicate the enrichment of ESR1-related gene networks among these IOP genes. Factors related with menarche, menopause, and oophorectomy have been associated with POAG. Genetic associations have been identified between sequence variants in estrogen receptor pathway genes and POAG. Estrogen and ESR1-related pathways including aromatase may affect the aqueous humor outflow facility and regulate IOP levels. The presence of estradiol in aqueous humor and ESR1 protein in the TM/SC region further supports the potential role of estrogen and ESR1-related pathways in IOP regulation. Based on our preliminary data on the elevated IOP levels from mouse models with the loss of Esr1 or Gper1 as well as their interaction with Nos3, we hypothesize that activation of estrogen signaling via ESR1 and GPER1 decreases IOP and POAG risk by modulating the turnover of extracellular matrix in the TM and the NO signaling in the SC. We propose to determine the in vivo effects of loss of estrogen signaling via Gper1 (Aim 1) or Esr1 (Aim 2) in murine eyes using tissue-specific knockout mice, and to determine the underlying mechanisms of Gper1 and Esr1-mediated IOP regulation using in vitro primary cell culture models (Aim3). Successful completion of this project will help reveal the critical role of estrogen signaling in aqueous outflow pathway and identify novel therapeutic targets to reduce IOP more effectively for this sight-threatening disease.