硝酸盐抑制细胞焦亡预防唾液腺放射损伤的作用和机制

头颈肿瘤放疗会导致唾液腺放射损伤，严重影响患者的生存质量。细胞焦亡在放射损伤中发挥了重要作用，抑制焦亡可以预防放射损伤。我们的前期研究发现，硝酸盐可以有效地预防唾液腺放射损伤。然而硝酸盐是否通过抑制细胞焦亡预防唾液腺放射损伤，以及硝酸盐抑制焦亡预防唾液腺放射损伤的机制尚不清楚。本研究拟通过细胞实验，开展放射线破坏线粒体功能激活mtROS/ox-mtDNA/NLRP3炎性小体/细胞焦亡通路的研究。通过小鼠下颌下腺放射损伤模型，开展mtROS/ox-mtDNA/NLRP3炎性小体/细胞焦亡通路激活导致唾液腺结构和功能破坏的研究。通过细胞和动物实验，研究在放射线照射条件下，硝酸盐调节线粒体功能、抑制焦亡通路、保护唾液腺结构和功能的机制。此外，通过硝酸盐转运蛋白基因敲除小鼠和基因沉默技术阻断硝酸盐转运验证这一机制。通过本研究揭示硝酸盐在预防唾液腺放射损伤中的生物学价值，并为临床转化奠定基础。

The radiation injury of salivary glands caused by radiation therapy seriously destroys the life quality of head neck cancer patients. Pyroptosis plays an important role on radiation injury to normal tissues. The inhibition of pyroptosis protects normal tissues against radiation injury. In our previous study, nitrate effectively prevented the radiation injury of salivary glands. However, it is not clear whether nitrate prevents the radiation injury of salivary glands by inhibiting pyroptosis and the mechanism of nitrate preventing radiation injury of salivary glands. In vitro study, it will be verified that radiation can destroy mitochondrial function and then activate the mtROS/ox-mtDNA/NLRP3 inflammasome/pyroptosis pathway on salivary gland acinar cells and vascular endothelial cells. On the mouse radiation model of submandibular glands, it will be studied that the activation of the mtROS/ox-mtDNA/NLRP3 inflammasome/pyroptosis pathway lead to damages of salivary gland structure and function. Then the mechanism of nitrate on inhibiting pyroptosis and preventing radiation injury of salivary glands via improving mitochondrial function will be explicated in vitro and vivo study. In addition, this mechanism will be further confirmed on sialin gene knockout mice and with gene silencing technique by blocking nitrate transporting. This study could reveal the biological value of nitrate on preventing the radiation injury of salivary glands and establish foundation on its clinical transformation.