维生素D通过Nrf2减少程序性坏死缓解放射性直肠损伤的机制研究

放射性直肠损伤降低盆腔肿瘤的放疗疗效及患者生活质量。我们前期证实，胚胎培养液对放射性直肠损伤具有缓解作用，发现其成分与Nrf2信号通路密切相关。深入研究发现，Nrf2抑制后，肠上皮细胞放射敏感性增高且小鼠放射性直肠损伤明显加重，程序性坏死相关蛋白水平也显著升高。在Nrf2正常表达情况下，维生素D处理明显改善肠上皮细胞程序性坏死及直肠组织损伤，但在Nrf2敲除情况下，维生素D对直肠损伤无显著影响，其详细机制尚不明确。为此我们提出假设，Nrf2可能调控影响肠上皮细胞的程序性坏死进而影响放射性直肠损伤，且很可能受维生素D的调控。为验证这一假设，我们将通过细胞模型、小鼠模型等手段，从分子、细胞、组织等多方面明确维生素D、Nrf2、程序性坏死及放射性直肠损伤的相互关系。本研究将从Nrf2介导的程序性坏死这个新视点为揭示放射性直肠损伤的发生机制进一步奠定基础，进而为放射性直肠炎的防治提供新思路。

Radiation-induced rectal injury is a major side-effect observed in patients with pelvic tumors. Previous studies demonstrated that the embryo culture medium can reduce radiation-induced rectal injury, and we found that its components are closely related to Nrf2 signaling pathway. Further studies showed that Nrf2 inhibition increased radiosensitivity of intestinal epithelial cells and aggravated mice rectal injury, and the level of necroptosis was also significantly increased. In addition, vitamin D treatment significantly improved intestinal epithelial cell necroptosis and rectal tissue injury under Nrf2 expression, while vitamin D had no significant effect on rectal injury when Nrf2 knockout. However, its detailed mechanism remains unclear. Here, we hypothesized that Nrf2 may regulate necroptosis of intestinal epithelial cells and thus affect radiation-induced rectal injury, which may be regulated by vitamin D and its related genes. To verify this hypothesis, we will clarify the relationship among vitamin D, Nrf2, necroptosis and radiation-induced rectal injury based on molecules, cells, tissues and animal experiments. This study aims to know the detailed mechanism of radiation-induced rectal injury related with Nrf2-regulated necroptosis, which may be good to prevent and treat radiation proctitis.