肝脏X受体激动剂干预β淀粉样蛋白诱导的视网膜炎性反应的作用及机制

Age-related macular degeneration (AMD) is leading cause of irreversible blindness in the elderly. Recent researches have revealed that activating liver X receptor (LXR) target gene ABCA1 may intervene AMD through promoting cholesterol outflow in macrophages. However, whether activation of LXR can inhibit the pathological process such as inflammation and cellular senescence involved in early AMD remains unknown. We hypothesize that activating LXR intervenes inflammatory responses and retinal pigment epithelium cell senescence in retinal inflammatory responses induced by amyloid beta (Aβ). The mechanism is through down regulation of cytokines, NLRP3 inflammasome and the downstream signal transduction factor NF-κB. Specific aims: 1) To clarify activating LXR ameliorates ocular inflammatory responses through down-regulating cytokines, NLRP3 inflammasome and its downstream signal transduction factor NF-κB signaling pathway. 2) To illuminate that activation of LXR target gene ABCA1 inhibits the inflammatory responses and aging changes induced by Aβ. 3) To verify whether there are abnormal expressions of LXR and ABCA1 in AMD patients. Our study will demonstrate whether malfunction of LXR-ABCA1 axis is involved in the pathogenesis of AMD and the mechanism of activation of LXR in the intervention of the inflammatory responses. The project will improve the understanding of the pathogenesis of AMD and may provide a novel avenue for the intervention of AMD.

年龄相关性黄斑变性是老年人首位致盲眼病，其发病机制与视网膜慢性低度炎症密切相关，对早期AMD目前尚无有效治疗方法。最近研究提示激活肝脏X受体(LXR)靶基因ABCA1可促进细胞胆固醇外流而干预晚期AMD的发展。但活化LXR是否可抑制早期AMD中β淀粉样蛋白引起的炎症反应尚属未知。假设：激动LXR可通过ABCA1下调炎性因子、炎性小体及NF-κB和MAPKs信号通路抑制β淀粉样蛋白诱导的视网膜炎症反应。目标：1）验证激动LXR可下调炎性因子、炎性小体及NF-κB信号通路抑制炎症反应。2）验证激动LXR抑制Aβ诱导的炎症反应是通过调节ABCA1实现的。3）检测早期AMD患者是否出现LXR及ABCA1的表达异常。意义：通过体内和体外实验对LXR抑制Aβ诱导炎症模型的研究，证实LXR-ABCA1轴在视网膜炎症中的作用机制并验证作用于LXR的抗炎新药，为深入理解AMD的机理提供新的科学依据。

年龄相关性黄斑变性是老年人首位致盲眼病，其发病机制与视网膜慢性低度炎症密切相关，对早期AMD目前尚无有效治疗方法。最近研究提示激活肝脏X受体(LXR)靶基因ABCA1可促进细胞胆固醇外流而干预晚期AMD的发展。但活化LXR是否可抑制早期AMD中β淀粉样蛋白引起的炎症反应尚属未知。假设：激动LXR可通过ABCA1下调炎性因子、炎性小体及NF-κB和MAPKs信号通路抑制β淀粉样蛋白诱导的视网膜炎症反应。目标：1）验证激动LXR可下调炎性因子、炎性小体及NF-κB信号通路抑制炎症反应。2）验证激动LXR抑制Aβ诱导的炎症反应是通过调节ABCA1实现的。3）检测早期AMD患者是否出现LXR及ABCA1的表达异常。意义：通过体内和体外实验对LXR抑制Aβ诱导炎症模型的研究，证实LXR-ABCA1轴在视网膜炎症中的作用机制并验证作用于LXR的抗炎新药，为深入理解AMD的机理提供新的科学依据。