新发现的TLR5受体激动剂-植物凝集素对肠道辐射损伤的保护作用与机制研究

Intestinal injury is an important aspect of radiation damage. Radiotherapy, especially for the abdominal and pelvic tumors,is often accompanied by severe side effects, the intestinal radiation injury. Clinically, except symptomatic and supportive treatment, there is no ideal treatment. TLR5 is a new target discovered to be closely related to radiation protection in recent years. Bacterial flagellin has been believed to be the only one agonist for TLR5. In the preliminary studies, we found that plant lectins are a new class of TLR5 agonists. Plant lectin PHA-L and WGA were tested and proved to be active to TLR5. This finding was confirmed by the latest report in scientific publication. Therefore, we hypothesized that the plant lectins with TLR5 agonist activity may have protective effects against intestinal radiation injury. This hypothesis was basically confirmed soon in our preliminary experiments. So far, the application of plant lectins in radiation protection and the related mechanisms, have not yet been reported. This project will evaluate the in vivo protective effects of plant lectins, PHA-L and WGA, against the intestinal radiation injury. And then we will detect the changes of molecules in TLR5-NFκB pathway to explore the related mechanisms at protein and gene level, by use of immunohistochemistry, RT-PCR and Western blot assay. At last, we will deeply analysis the mechanism of the interaction of plant lectins towards TLR5, by application of computer molecular simulation technologies.The work of this project will deepen the understanding of the mechanism of intestinal radiation injury, and provide the new targets and approaches for the clinical treatment of radiation enteritis. And the work on the plant lectin PHA-L and WGA will also lay an experimental fundation for the development of new radioprotectors.

肠道是辐射损伤的重要靶器官。近年来的研究表明TLR5受体与辐射防护尤其是肠道辐射损伤的保护密切相关。在前期研究中，我们发现几种植物凝集素具有TLR5激动活性，是一类全新的TLR5激动剂。这一结果被最新发表在国际权威期刊上的研究报告证实。在预实验中，我们首次对具有TLR5激动活性的植物凝集素PHA-L和WGA的辐射防护作用进行了研究，发现二者对小鼠具有十分显著的辐射防护效果。因此，本项目将进一步对植物凝集素PHA-L和WGA小鼠肠道辐射损伤的保护作用进行评价，并明确最佳给药方案；利用分子生物学手段检测小肠细胞凋亡以及TLR5-NFκB通路的变化规律，探讨其作用机制；通过计算机分子模拟技术深度解析植物凝集素与TLR5的相互作用，研究植物凝集素的构效关系。这些工作的开展将加深对肠道辐射损伤机理的了解，为临床放射性肠炎的治疗提供新的靶点和途径，也为新型辐射防护药物的开发奠定实验基础。

放射性肠炎是放射治疗尤其是腹腔盆腔部放疗的常见毒副作用，而肠道也是辐射损伤的重要靶器官。近年来的研究表明TLR5受体与辐射防护尤其是肠道辐射损伤的保护密切相关。在前期研究中，我们发现几种植物凝集素具有TLR5激动活性，是一类全新的TLR5激动剂。本项目通过反复的实验验证，结果表明植物凝集素PHA-L对小鼠肠道辐射损伤具有明显的保护作用。在此基础上我们不断深入研究，明确了植物凝集素PHA-L的最佳给药剂量；利用分子生物学手段确证了PHA-L对TLR5受体的激活和刺激作用，探讨了作用机制；通过计算机分子模拟技术深度解析了植物凝集素PHA-L与TLR5的相互作用的结合模式。这些工作的开展加深了我们对肠道辐射损伤机理的了解，为临床放射性肠炎的治疗提供可能的靶点和途径，也为新型辐射防护药物的开发奠定了一定的实验基础。