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。我们在前期工作中发现HMGB1是放射性肠炎的重要介导因素。TLR4/MD-2是HMGB1激活下游炎症通路的重要受体，也与放射性肠道损伤机制中的细胞程序性坏死有密切联系。抑制MD-2可有效治疗或缓解HMGB1介导的炎性疾病的发生发展，也可以逆转TLR4激活诱导的细胞程序性坏死，因此，我们认为靶向MD-2是防治放射性肠炎一种新的思路和途径。在前期工作的基础上，我们筛选找到了三个MD-2特异性结合抑制小肽，其中两个为国内外首次发现，并观察到它们对细胞程序性坏死的抑制活性。在本项目中，我们将在体外体内两个方面研究MD-2对防治放射性肠炎的重要意义，研究MD-2基因敲除以及MD-2抑制性小肽对肠道辐射损伤产生的影响，以及与细胞程序性坏死之间的联系，并结合计算机分子模拟技术深入探讨相关机制，以期为放射性肠炎的临床治疗提供新的治疗思路和药物候选。

Radiation entities are common side effects in radiotherapy, especially for the abdominal and pelvic tumors. Recent studies showed that HMGB1 is a major risk factor for inflammatory bowel disease. Our preliminary studies suggested that HMGB1 is an important pathogenic factor or mediator in radiation enteritis. TLR4 is a major receptor for HMGB1 and MD-2, as a co-receptor, is required for HMGB1 binding to TLR4. HMGB1 fails to activate TLR4 in the absence of MD-2 or if MD-2 is inhibited. Subsequently, the downstream inflammatory pathways will be blocked. TLR4/MD-2 was also deemed the important receptor to trigger Necroptosis, a kind of programmed cell death involved in the mechanisms of radiation entities. It was tested that inhibiting MD-2 can block necroptosis induced by activating TLR4.Therefore, we think it will be a new way to prevent or treat radiation entities by targeting MD-2. Based on our prior work, three small peptides were screened out for binding MD-2. Two of them are new discoveries at the first time. We observed that these small peptides can inhibit necroptosis in vitro. In this study, we will investigate the potential role of targeting MD-2 to treat radiation enteritis using both in vitro and in vivo models. We will use MD-2 gene knockout and MD-2 binding inhibitory small peptides to examine their influences to radiation damage of intestinal cells in vitro and radiation enteritis in vivo, and find the relationship between MD-2 and Necroptosis. In addition, we will perform computational molecular dynamics analysis to explore the potential mechanisms. Our study will possibly shed a light on the clinical treatment of radiation enteritis, or offer new therapeutic drug candidates.