肠黏膜炎是临床肿瘤病人化疗过程中比较常见的副作用。申请人已经证实5-FU主要诱导小肠隐窝第4-7位干祖细胞凋亡，IL-1Ra可用于治疗化疗肠黏膜炎。因为肠上皮干细胞是肠上皮更新代谢与损伤修复的主要细胞来源，所以我们将研究的中心放在了肠上皮干细胞上：首先，在化疗小鼠肠黏膜损伤修复模型上，研究肠上皮干细胞的凋亡与化疗肠黏膜炎的关系，并探讨IL-1Ra抑制肠上皮干细胞凋亡的机制；其次，在PUMA-/-化疗小鼠肠黏膜损伤修复模型上，研究PUMA及其主要相关信号通路PI3K/Akt/p53在IL-1Ra抑制肠黏膜干细胞凋亡中的作用；最后，建立肠上皮干细胞系，从体外深入研究IL-1Ra通过调控PUMA的表达影响PI3K/Akt/p53信号通路来抑制5-FU作用后肠上皮干细胞凋亡的机制。该研究对进一步揭示化疗肠黏膜损伤的分子机制、设计合理的治疗药物及判断预后，提高化疗患者生活水平具有重要意义。

Intestinal mucositis is a common chemotherapy-induced complication. The applicant had confirmed that 5 - FU mainly induced the ancestral stem cells apoptosis, which located at positions 4–7 of the small intestinal crypt, and IL-1Ra suppressed 5-FU-induced apoptosis in vitro. Because ancestral stem cells in the small intestinal crypt are the source of intestinal cell metabolism and regeneration, we focus on the intestinal ancestral stem cells. First of all, we will study the relationship between the ancestral stem cells apoptosis and intestinal epithelial stem cells apoptosis on chemotherapy-induced intestinal mucositis mice model and the effect ofIL-1Ra. Second, we will study the effect of PI3K/Akt/p53 on the chemotherapy-induced intestinal mucositis. Finally, we will establish the intestinal ancestral stem cells lines and study the effect of PI3K/Akt/p53 signaling pathway on it. The study is to reveal the molecular mechanism of chemotherapy-induced intestinal mucosa damage. It can be help to design reasonable treatment and judging prognosis, and improve the level of chemotherapy-induced intestinal mucositis patients.