Department of Ophthalmology and Department of Anatomy, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
Nat Commun. 2021 Aug 12;12(1):4877. doi: 10.1038/s41467-021-25181-7.
Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P = 4.73 × 10), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.
慢性升高的眼内压（IOP）是原发性开角型青光眼的主要危险因素，而原发性开角型青光眼是导致失明的主要原因之一。小梁网（TM）的功能障碍是导致IOP 升高的主要原因，TM 控制房水（AqH）从前房流出。在这里，我们证明缺乏 Krüppel 样锌指转录因子 GLI 样蛋白-1（GLIS1）的小鼠会出现慢性升高的 IOP。磁共振成像和组织病理学分析显示，GLIS1 表达的缺失会诱导 TM 进行性退化，导致 AqH 从前房排出效率降低，IOP 升高。转录组和顺式作用元件分析鉴定了几个与青光眼和细胞外基质相关的基因是 GLIS1 的直接转录靶点。我们还发现 GLIS1 变体 rs941125 与人类青光眼之间存在显著关联（P=4.73×10），这进一步支持了 GLIS1 在青光眼发病机制中的作用。我们的研究确定 GLIS1 是 TM 功能和维持、AqH 动力学和 IOP 的关键调节因子。
Zotero 插件
