PAX8阳性星形胶质细胞在视乳头盘沿缺失及轴突退变中的作用及机制

视乳头盘沿（NRR）缺失导致的视神经退变是青光眼高眼压（eIOP）重要病理特征。NRR主要由星形胶质细胞（AS）构成，在视神经退变之前，NRR-AS就已激活，但机制至今不明。我们前期首次发现NRR存在PAX8特异性AS。在eIOP模型中，PAX8阳性AS首先在NRR边缘激活迁移。通过转录组测序对比PAX8阴性AS，发现PAX8阳性AS的Yes相关蛋白（YAP）基因显著富集。鉴于YAP是AS激活重要调控分子，我们推测PAX8阳性AS可能通过YAP在NRR病理进程中发挥关键作用。为此本项目应用已繁育的pax8-CreER;yapf/f小鼠，采用eIOP模型，利用细胞和分子生物学手段，揭示PAX8阳性AS生物学特征，阐明YAP调控PAX8阳性AS激活效应及机制，最终揭示eIOP病理进程中NRR缺失和视神经退变的原因。可望为NRR-AS研究奠定实验基础，为青光眼视神经退变研究提供新靶点和理论依据。

Astrocytes (AS) play important roles in the degeneration of optic nerve in glaucoma. Before the degeneration of the optic nerve, the AS of the neuroretinal rim tissue (NRR) migrated and disturbed, but the mechanism is still unknown. We have sequenced AS by single cells sequence from different regions of the human central nervous system, and found that a group of NRR's AS specifically express pax8. In elevated intraocular pressure model, we observed pax8 positive ASs migrate first. By comparing the pax8 negative and positive ASs with RNA-seq sequencing, it was found that the YAP signal of pax8 positive AS was significantly enriched. Given that YAP is an important regulator of AS migration and differentiation, we speculate that pax8-positive AS may play a key role in the pathology of NRR through YAP. To this end, the project plans to apply the existing pax8-CreER;yapf/f mice to study the biological characteristics of this subpopulation of cell through developmental biology methods; to use an elevated intraocular pressure model to study the cellular mechanism of NRR thinning and axonal degeneration; to clarify the mechanism of YAP regulation of pax8-AS migration and related axon degeneration by application of molecular biology methods; to regulate the YAP activity of pax8-As to further reduce the loss of NRR. In sum our project provides a new target and theoretical basis for the study of glaucomous optic nerve degeneration and NRR thinning.