鞘氨醇-1-磷酸受体1调节剂对放射引起的骨髓造血组织损伤的防治作用及其机制研究

The prevention and treatment of Bone Marrow form of Acute Radiation Sickness(BM-ARS) is still the focus of Radiological Medcine study currently. However, it is difficult to carry out targeted drug design because the targets are not clear enough or mechanisms are unclear of the fielded drugs or drugs in research. In our experiments, we demonstrated that, singosine-1-phosphate receptor 1 (S1PR1) agonists FTY720 had significant radioprotective effects on radiation-induced bone marrow hematopoietic tissue injury. Application of selective agonists and antagonists of S1PR1 initially clarified that S1PR1 may be the targets of S1PR1 regulators in preventing and treating BM-ARS. To pursue this possibility, in this project we will further demonstrate the radioprotective efficacy on hematopoietic system injuries; and use S1PR1 selective agonists, antagonists and conditionally knock-out mice to confirm the targets and find the major effector cells. We believe our research will provide new tools on development of promising candidate radioprotective agents and new insights in the advancement of radioprotective mechanisms. The study is expected to reveal a new mechanism for the pathogenesis of acute radiation sickness and found a new target for prevention and treatment of acute radiation sickness, which have important theoretical value and practical significance for radioprotective drugs development based on new targets.

当前骨髓型急性放射病（BM-ARS）的防治依然是放射医学研究的重点，而目前列装的抗放药及多数在研的抗放药物或作用机制不清，或作用靶点不够明确，难于开展靶向药物设计研究。我们通过前期的研究发现，鞘氨醇1-磷酸受体1（S1PR1）激动剂FTY720对放射引起的骨髓造血组织损伤有显著的防治作用；应用S1PR1选择性激动剂及拮抗剂初步明确了S1PR1很可能是其作用靶点。本项目拟进一步完善S1PR1调节剂防治BM-ARS的效应及其促进照后造血恢复的机制研究；应用S1PR1选择性激动剂、拮抗剂及条件敲除小鼠进行靶点的确证研究；应用S1PR1条件敲除小鼠模型探索 S1PR1调节剂防治BM-ARS的主要效应细胞。该研究有望揭示ARS发病新机制、发现ARS防治新靶点，对基于新靶点的抗放药物研发具有重要的理论价值和实际意义。