TLR2/4/5共同激动剂HKST对不同LET辐射的防治作用及机制

核恐怖袭击和核事故中存在大量的高、低LET辐射，其医学防治是放射医学亟待解决的关键问题。2008年Science上报道了TLR5激动剂具有辐射防护效果，随后我们发现TLR2、4、9具有辐射防治作用。但不同TLR可识别不同的病原，启动特异性下游通路;TLRs在不同组织表达丰度不同，因此单独激活某一TLR辐射防护效果有限。热灭活伤寒沙门菌（HKST）是高效的 TLR2/4/5的共同激动剂，我们发现其具有很好的辐射防护效果。本项目拟从分子、细胞、辐射敏感组织和整体动物多个层次，进一步探索HKST对γ射线和12C6+重离子辐射损伤的防治作用；并用基因敲除小鼠和CRISPR基因敲除技术探讨TLR2、TLR4、TLR5及其下游信号分子TRIF、MyD88等的作用机制；使用CRISPR筛选文库寻找HKST辐射防护新靶点。该研究将为高、低LET辐射防治提出新的理论和实验依据，为辐射防护寻找新的靶点和途径。

Protection against high- and low- LET radiation is one of the most critical problems in radiation medicine, which is very common in nuclear attacks and accidents. In 2008, the radioprotective effects of TLR5 agonist CBLB502 was reported in Science, after then we found that activation of TLR2, TLR4 and TLR9 exerted effects against ionizing radiation. However, different TLRs recognize different proportion of pathogens, and initiate different downstream signaling pathways. What’s more, the expression levels of different TLRs were different in specific tissues, so it may not be effective enough to activate any single TLR receptor. Surprisingly, Heat Killed Salmonella typhimurium (HKST) have the capacity of activating TLR2, TLR4 and TLR5 signaling pathway synchronously, which was proved in many studies. In this study, we are aimed to investigate the protective effects of HKST on cells and animals against γ ray and 12C6+ heavy particle irradiation in molecular, cellular, tissue and animal levels. TLR2/4/5 knockout (KO) mice and CRISPR-Cas9 based KO of TLR downstream pathways were used to uncover the mechanism underlying the radioprotective effects of HKST. We also used a CRISPR screening library to screen novel targets of HKST, which might be novel mechanism of radioprotection. Our study will provide novel experimental support for the protection of high- and low- LET radiation and provide novel targets and strategies for radiation protection.