异染色质对视网膜色素上皮细胞中IL17RA等炎症因子在氧化应激下的转录调控

氧化应激所致视网膜色素上皮细胞(RPE)变性死亡和炎症反应是年龄相关性黄斑变性(AMD)的重要病因。我们已证明:有转录抑制属性的异染色质沉默凋亡基因，在氧化应激中保护RPE;氧化应激上调白介素17受体IL17RA，降低IL17RA抑制炎症和细胞凋亡；转录因子KLF4结合IL17RA启动子激活其转录。预实验显示:异染色质在有KLF4结合位点的IL17RA启动子富集;破坏异染色质激活IL17RA及下游炎症因子。因此，我们首次提出：在氧化应激中，异染色质通过抑制IL17RA的转录抑制RPE炎症反应、增加细胞活性。项目将利用转基因小鼠、已筛得药物和AMD病人资源，明确氧化应激下异染色质：1）是否抑制RPE炎症反应；2）是否通过IL17RA调控炎症反应；3）是否通过KLF4调控IL17RA的转录；以及4）AMD发展中异染色质与RPE氧化损伤和炎症反应的相关性。结果将为AMD治疗提供新信息和新靶点。

Oxidative stress (OS)-induced retinal pigment epithelium (RPE) inflammation and cell apoptosis are critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause for blindness in the elderly. Our recent studies show that OS induces formation of highly condensed, transcription repressive heterochromatin. This newly formed heterochromatin protects RPE from oxidative damage by selectively silencing the p53-mediated apoptotic signaling pathway. In addition, we have identified that interleukin 17 receptor A (IL17RA) as one of the most dramatically upregulated inflammatory genes upon OS exposure. Silencing of IL17RA inhibited OS-induced inflammatory response and RPE cell apoptosis. Our preliminary data showed that heterochromatin was enriched in the promoter of IL17RA. Pharmaceutical perturbation of heterochromatin induced IL17RA and its downstream inflammatory gene expression. Therefore, we hypothesize that heterochromatin represses RPE inflammatory response and promotes cell viability through suppressing IL17RA transcription. In this project, with the obtained genomics and transcriptomics data, the constructed HP1α and Suv39h1 heterochromatin gene knockout mice, the selected heterochromatin-promoting molecule and the abundant AMD patient resources in Zhongshan ophthalmic center, we are aimed to elucidate the in vivo functional mechanisms of heterochromatin in OS-induced RPE inflammatory response and cell apoptosis. We believe this research will reveal novel information for AMD pathogenesis and substantiate the scientific basis for establishing heterochromatin as a new target for AMD treatment.