Nrf2/HO-1信号轴介导铁死亡参与视网膜缺血再灌注损伤的机制研究

Retinal ischemia-reperfusion injury (RIRI) is a common pathological basis for glaucoma, diabetic retinopathy and other related eye diseases, which can lead to impaired visual function and eventually blinding, and its mechanism has not been elucidated. Our previous studies have found that ferroptosis inhibitors have a protective effect on retinal ganglion cell death after retinal ischemia-reperfusion, but the mechanism is unclear. Therefore, we speculate that ferroptosis involved in retinal ischemia-reperfusion injury，and Nrf2/HO-1 signal axis may have a regulatory effect on the ferroptosis of retinal ganglion cells.To confirm this hypothesis, we will replicate the acute retinal ischemia-reperfusion model at both the whole and cell levels, using molecular biology, electron microscopy, flow cytometry, RNAi and other techniques to observe the retinal ganglion cell morphology,ferroporisis marker protein expression and the change of oxygen free radicals in the process of retina ischemia-reperfusion injury. The effect of regulating Nrf2/HO-1 pathway on ferroptosis of retinal ganglion cells will be observed. This topic will elucidate the mechanism of retinal ischemia-reperfusion from a new perspective, and provide a new target for the prevention and treatment of retinal diseases.

视网膜缺血再灌注损伤（retinal ischemia reperfusion injury，RIRI）是青光眼、糖尿病视网膜病变及其他相关眼病共同的病理基础，可导致视功能的损害并最终致盲，其机制尚未阐明。我们的前期研究发现铁死亡抑制剂对视网膜缺血再灌注后视网膜神经节细胞死亡具有保护作用。因此，我们提出假设：铁死亡参与了视网膜缺血再灌注的机制，Nrf2/HO-1信号轴可能对视网膜神经节细胞铁死亡具有调控作用。为了证实这一假说，本课题拟在动物和细胞两个水平复制急性视网膜缺血再灌注模型，采用分子生物学、电镜、流式细胞仪、RNAi等技术，观察视网膜神经节细胞形态，铁死亡标志蛋白的表达以及氧自由基的变化等指标；并观察Nrf2/HO-1信号轴对视网膜神经节细胞铁死亡的影响。本课题将从新的视角阐明视网膜缺血再灌注的机制，为防治视网膜疾病提供新靶点。

视网膜缺血再灌注（ischemia/reperfusion injury，IR）与很多眼部疾病都相关，视网膜I/R会导致视网膜神经节细胞（retinal ganglion cells，RGCs）死亡，视网膜形态改变、功能丧失，最终导致视觉丧失，严重影响患者的生活质量。铁死亡（Ferroptosis）是一种铁依赖性的，区别于细胞凋亡、细胞坏死、细胞自噬的新型的细胞程序性死亡方式。本研究围绕铁死亡与视网膜缺血再灌注损伤开展研究，证实铁死亡参与了视网膜缺血再灌注损伤。本研究在细胞和动物水平验证铁死亡参与视网膜缺血再灌注损伤过程。证明应用铁死亡抑制剂对视网膜缺血再灌注损伤具有保护作用，进一步发现NCOA4可能调控铁死亡相关蛋白FTH、FTL、GPX4，参与视网膜缺血再灌注损伤过程。本研究为视网膜缺血再灌注损伤的治疗提供了理论基础和新的药物靶点。