PAX2 在年龄相关性黄斑变性发生发展过程中分子机制的研究

Age-related macular degeneration is becoming the leading cause of blindness in elder people in China, and oxidative injury plays a main role in contributing to AMD.. In the classical experiments simulating AMD in vitro, applicant has found that the expression of PAX2 expression is down-regulated significantly. While over expression of PAX2 increases cells’ resistance to oxidative injury, low expression of PAX2 by shRNA reduces the resistance. Those data suggest PAX2 may involve in the development of AMD. Besides, there has been no report about the function of PAX2 in AMD pathogenesis so far. . Based on the applicant’s previous research, we first focus on the regulatory network of PAX2. We will study the function of PAX2 in all respects, including upstream cis-acting elements, trans-acting factors, protein complexes LncRNAs, the promoter location which PAX2 attach to and the downstream pathway of PAX2. Then, using three AMD pathogenesis models, we analysis the change of the PAX2 regulatory network before and after oxidative injury, trying to find out the checkpoint of oxidative injure. At last, we will confirm our results and double-check the function of PAX2 regulatory network in AMD patients.. This research will disclose the molecule mechanism of PAX2 in AMD pathogenesis, which will offer molecular evidence for AMD early diagnosis, treatment or intervention.

年龄相关性黄斑变性(Age-related macular degeneration，AMD)即将成为国内老年人致盲的首要病因，而诱发 AMD 的主要机制是氧化损伤。. 在模拟 AMD 发生环境的经典实验中，申请者发现 PAX2 表达水平显著降低； 过表达PAX2可增加细胞对氧化损伤的抵抗；下调则降低细胞的抵抗。提示 PAX2 可能参与了 AMD 的发生发展，但至今尚无 PAX2 在 AMD 相关方面的报道。. 基于以往的研究基础，本课题拟先从PAX2基因与蛋白两个层次着手，分析其调控网络，全局性了解 PAX2 的功能；然后在模拟 AMD 发生发展的细胞模型中，分析 PAX2 调控网络在氧化损伤前后的变化，找出氧化损伤的关键节点；最后在AMD患者的临床样品中验证这些关键节点的作用。. 本研究将为AMD的早期诊断、治疗或干预提供一定的分子依据。

氧化损伤是年龄相关性黄斑变性的病变基础，本课题主要集中在氧化损伤通路及药物的作用机理。. 在RPE细胞氧化损伤的的模型中，发现了ID2通过p-ERK1/2-ID2-NRF2信号通路，保护RPE细胞（Arch Biochem Biophys. 2018; 650: 1-13）；发现在RPE细胞中，PTEN能够降低UVB诱导的氧化损伤（Biomed Res Int. 2017; 2017: 3681707）；METTL3通过调节PI3K/AKT/mTOR信号通路，促进视网膜母细胞瘤的发展进程，这一结果可能为视网膜母细胞瘤的靶向治疗方案提供了另一种选择(J Cell Mol Med. 2020; 24: 12368-78)；下调NOTCH2的表达，通过上调PTEN、下调β-catenin及维持P21胞内平衡的方式，保护RPE(Mol Med Rep. 2017; 16: 730-736)； HES1激活PARP1并调节AIF的亚细胞定位以介导多柔比星处理下的凋亡反应，在癌症治疗中Notch信号通路可能与多柔比星协同作用(Cancer Manag Res. 2018; 10: 1439-1448)。. 药物进一步研究发现，川芎嗪(TMP)通过ATF4介导PRP聚集抑制从而缓解细胞内质网应激，从而保护视网膜感光细胞（J Mol Med (Berl). 2021 Jan 7 ）；叶黄素增强RPE细胞抗氧化应激能力，或可用于预防AMD，降低AMD发展的风险(Mol Med Rep. 2017;16: 2069-2074)；THZ1可能成为预防和治疗后发性白内障的新药物(J Cancer. 2019; 10: 3778-3788)。. 本研究已为年龄相关性黄斑变性的早期诊断、治疗干预提供一定的分子依据。