Estrogen and its Receptor in Intraocular Pressure Regulation

摘要 此应用的目标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) – 通过调节眼内压 (IOP) 小梁网 (TM) 和施累姆氏管 (SC) 内皮细胞。 IOP 是主要且唯一可修改的 临床上原发性开角型青光眼 (POAG) 患者的危险因素。 TM 和 SC 调制 大多数房水流出阻力在常规途径中。尽管进行了大量研究 尽管 TM/SC 流出动力学方面取得了进展，但可用于调节传统治疗的治疗靶点有限 流出。有必要确定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已确定 >150 IOP- 相关的基因组位点太多，无法进行功能追踪。我们全面的生物信息学 对这些 IOP 相关基因组位点的分析表明 ESR1 相关基因网络的富集 在这些 IOP 基因中。与初潮、绝经和卵巢切除术相关的因素已被研究 与 POAG 相关。雌激素序列变异之间的遗传关联已被确定 受体途径基因和 POAG。雌激素和 ESR1 相关途径（包括芳香酶）可能会影响 房水流出设施并调节眼压水平。房水中存在雌二醇和 TM/SC 区域的 ESR1 蛋白进一步支持雌激素和 ESR1 相关途径的潜在作用 在眼压调节中。基于我们关于小鼠模型眼压水平升高的初步数据 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 通过 ESR1 和 GPER1 通过调节细胞外基质的周转来降低 IOP 和 POAG 风险 SC 中的 TM 和 NO 信号传导。我们建议确定雌激素信号丧失的体内影响 使用组织特异性敲除小鼠在鼠眼中通过 Gper1（目标 1）或 Esr1（目标 2），并确定 使用体外原代细胞培养模型研究 Gper1 和 Esr1 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房水中的关键作用 流出途径并确定新的治疗靶点，以更有效地降低眼压，以应对这种威胁视力的情况 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.