S1P受体激动剂FTY720防治肠型急性放射病的分子细胞学机制研究

Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the intestinal form of acute radiation sickness (IARS). In contrast to the hematopoietic syndrome, no medical countermeasures are approved to prevent or treat IARS. Despite decades of study, the critical cellular targets of radiation-induced toxicity in the GI tract and the molecular mechanism of cell death underlying the IARS remain controversial. Based on the previous research findings and latest advance, we put forward the idea that the damage to the organ parenchymal cells and microenvironment coexist in the pathogenesis of the acute radiation sickness, paying equal attention to the protection against radiation injury of organ parenchymal cells and the mitigation of damage to organ microenvironment for the treatment of acute radiation sickness. In search of measures to alleviate radiation- induced vascular damage, the role of S1P receptor agonist FTY720 for prophylaxis and treatment of IARS was found. According to our preliminary work, it is suggested that S1P1 (sphingosine-1- phosphate receptor 1) may be the target of FTY720 for the treatment of IARS. So, in this project, the therapeutic effect of FTY720 for the treatment of IARS will be evaluated using many species of animal models, including mice, beagle dog or monkey. Then, the radioprotective effect of FTY720 on intestinal stem cells will be assayed in previously established Lgr5, bmi1 or Hopx knockin mouse models. Chemical probes for S1P1, such as its agonists or antagonists, will be used to find the role of S1P1 activation in the treatment of IARS with FTY720. By breeding of S1P1 conditional knockout mice with Tie2-Cre, Tg(Lck-cre) or Pvillin-cre mice to produce the filial generation with S1P1 gene partly or all deleted in vascular endothelial cells, lymphocytes or intestinal epithelial cells, we would explore the relationship between the radioprotective effects of FTY720 and S1P1 expression in endothelial cells, examine the role of the migration of lymphocyte to intestine in the pathogenesis of the IARS, which was regulated by the S1P concentration, and exclude the possible affects of S1P1 expressed in intestinal epithelial cells. Above all, in order to provide theoretical basis for drug discovery and development against IARS or radiation enteritis, the molecular cytological mechanism of FTY720 for prophylaxis and treatment of IARS will be revealed.

肠型急性放射病（IARS）病情重，病程短，目前尚缺乏有效的防治措施。本课题提出"器官实质细胞与微环境损伤在急性放射病发病中并存，在救治上并重"的理念；并在该理念的指导下，发现了S1P受体激动剂FTY720对IARS的防治作用。前期工作提示，S1P1可能是FTY720防治IARS的药靶。据此，本课题拟应用小鼠、比格犬等多种动物模型评价FTY720防治IARS的疗效；应用小肠干细胞标记基因敲入小鼠研究FTY720对小肠干细胞放射损伤的防护作用；应用化学小分子探针了解S1P1激活在FTY720防治IARS中的作用；应用条件性敲除小鼠探讨FTY720防护作用与血管内皮细胞S1P1表达关系，分析受S1P1调节的淋巴细胞募集在IARS发生中的作用，并排除肠上皮细胞S1P1激活的影响。最终揭示FTY720防治IARS的分子细胞学机制，为IARS相关药物研发以及放射性肠炎的临床救治药物研究提供理论依据。

肠型急性放射病（IARS）病情重，病程短，目前尚缺乏有效的防治措施。本课题提出“器官实质细胞与微环境损伤在急性放射病发病中并存，在救治上并重”的理念；并在该理念的指导下，发现了S1P受体激动剂FTY720对IARS的防治作用。本课题基于前期发现S1P1可能是FTY720防治IARS的药靶，应用小鼠、比格犬等多种动物模型系统评价了FTY720防治IARS的疗效，确定了FTY720的最佳给药方案及防护的最适辐照剂量；应用小肠干细胞标记基因敲入小鼠研究FTY720对小肠干细胞放射损伤的防护作用，发现Lgr5+干细胞在小肠隐窝再生方面的重要作用；应用化学小分子探针了解S1P1激活在FTY720防治IARS中的作用；应用条件性敲除小鼠探讨FTY720防护作用与血管内皮细胞S1P1表达密切相关，并排除肠上皮细胞S1P1激活的影响。研究揭示了FTY720防治IARS的分子细胞学机制，为IARS相关药物研发以及放射性肠炎的临床救治药物研究提供了理论依据，为急性放射病发病机制的探索提供了新的理论基础。