视网膜色素上皮
细胞生物学
视网膜
上皮-间质转换
核受体
生物
表型
黄斑变性
视网膜变性
视网膜
激活剂(遗传学)
转录因子
癌症研究
受体
下调和上调
医学
遗传学
基因
生物化学
神经科学
眼科
作者
Pei‐Li Yao,Vipul M. Parmar,Mayur Choudhary,Goldis Malek
标识
DOI:10.1073/pnas.2202256119
摘要
Phenotypic variations in the retinal pigment epithelial (RPE) layer are often a predecessor and driver of ocular degenerative diseases, such as age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We previously identified the orphan nuclear receptor-related 1 (NURR1), from a nuclear receptor atlas of human RPE cells, as a candidate transcription factor potentially involved in AMD development and progression. In the present study we characterized the expression of NURR1 as a function of age in RPE cells harvested from human donor eyes and in donor tissue from AMD patients. Mechanistically, we found an age-dependent shift in NURR1 dimerization from NURR1-RXRα heterodimers toward NURR1-NURR1 homodimers in primary human RPE cells. Additionally, overexpression and activation of NURR1 attenuated TNF-α–induced epithelial-to-mesenchymal transition (EMT) and migration, and modulated EMT-associated gene and protein expression in human RPE cells independent of age. In vivo, oral administration of IP7e, a potent NURR1 activator, ameliorated EMT in an experimental model of wet AMD and improved retinal function in a mouse model that presents with dry AMD features, impacting AMD phenotype, structure, and function of RPE cells, inhibiting accumulation of immune cells, and diminishing lipid accumulation. These results provide insight into the mechanisms of action of NURR1 in the aging eye, and demonstrate that the relative expression levels and activity of NURR1 is critical for both physiological and pathological functions of human RPE cells through RXRα-dependent regulation, and that targeting NURR1 may have therapeutic potential for AMD by modulating EMT, inflammation, and lipid homeostasis.
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