Estrogen and its Receptor in Intraocular Pressure Regulation

摘要 这项应用的目的是确定雌激素及其受体-雌激素受体1(ESR1)的作用。 和G蛋白偶联雌激素受体(GPER1)-通过 小梁网络(TM)和Schlemm管(SC)内皮细胞。眼压是主要的，也是唯一可以修改的 临床上影响原发性开角型青光眼患者的危险因素。TM和SC调制 大部分房水流出阻力在常规通路中。尽管有重要的研究 TM/SC流出动力学研究进展--用于调节常规TM/SC流出动力学的靶点有限 外流。有必要寻找新的靶点来更有效地降低青光眼患者的眼压 进行性视野丧失。最近的几项全基因组关联研究发现，&gt；150眼压- 相关的基因组基因座太多，功能上无法跟进。我们全面的生物信息学 对这些眼压相关基因组位点的分析表明，ESR1相关基因网络丰富 在这些眼压基因中。与月经初潮、更年期和卵巢切除有关的因素 与POAG有关。雌激素中的序列变异之间的遗传关联已经被确定 受体途径基因与POAG。雌激素和包括芳香酶在内的ESR1相关通路可能影响 房水流出设施和调节眼压水平。房水中雌二醇的存在和 TM/SC区的ESR1蛋白进一步支持雌激素和ESR1相关通路的潜在作用 在眼压调节方面。根据我们的初步数据，高眼压水平的小鼠模型与丢失 ESR1或Gper1以及它们与NOS3的相互作用，我们假设雌激素信号的激活 Via ESR1和GPER1通过调节眼内细胞外基质的周转降低IOP和POAG的风险 TM和SC中的NO信号。我们建议确定雌激素信号丢失对体内的影响。 通过Gper1(Aim 1)或ESR1(Aim 2)通过组织特异性基因敲除小鼠的眼睛，并确定 用体外原代细胞培养模型研究Gper1和ESR1介导的眼压调节机制 (目标3)。该项目的成功完成将有助于揭示水中雌激素信号的关键作用。 外流途径和寻找新的治疗靶点以更有效地降低这种威胁视力的眼压 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.