米诺霉素抑制脓毒症引起TECs死亡的机制研究

胸腺上皮细胞（TECs）对T细胞发育起决定性作用。脓毒症引起TECs大量死亡，导致T细胞阳性、阴性选择缺失，输出量和TCR库容持续减少。患者对肿瘤、自身免疫病和传染病高度易感。我国每年有400多万脓毒症康复患者面临这一风险。故阐明脓毒症引起TECs死亡机制，寻找关键靶点药物迫在眉睫。文献报道TECs退化与NLRP3介导的焦亡相关。我们在脓毒症模型中发现米诺霉素对TECs有很强保护作用，经预测其作用于RIPK1，故脓毒症引起的TECs死亡与焦亡、坏死性凋亡相关。文献报道和我们研究发现米诺霉素和强力霉素上调Trx2表达，而Trx2可抑制TXNIP、MLKL，据此推测米诺霉素可抑制RIPK1，上调Trx保护TECs。本研究拟采用细胞与分子生物学技术，重点研究脓毒症引起TECs死亡机制和米诺霉素保护TECs的机制，为临床防治脓毒症引起的TECs死亡开辟新的路径，因此具有重要的理论和和临床意义。

Thymic epithelial cells (TECs) play a critical role in the development of T cells. It has been declared that the sepsis leads to thymus acute atrophies, massive immature T cells and TECs death. It also results in the loss of positive and negative selection of T cells with less TECs and the continue declining of T cells output and TCR library. Every year, more than 4 million patients who recovered from sepsis are at high risk of tumors, autoimmune diseases and infectious diseases in our country. Therefore, it is great significance and extremely urgent to clarify the mechanism of TECs death caused by sepsis, find the drugs against the key target to protect TECs. It has been reported that the senescence of TECs is related to NLRP3 mediated pyroptosis. We found that minocycline has a strong protective effect on TECs in sepsis animal model. RIPK1, one of the key kinases of necroptosis, may be the target of minocycline which is predicted by bioinformatics and the molecular operating environment software. So, we speculate that the TECs death induced by sepsis is related to pyroptosis and necroptosis. We also found that the expression of Trx2 could be up-regulated by doxycycline to protect TECs from mitomycin-induced apoptosis. It has been reported that minocycline can up-regulate Trx2 expression, while Trx2 can inhibit TXNIP binding with NLRP3 and the oligomerization of MLKL. So, let's assume that the minocycline can protect TECs from pyroptosis and necroptosis via inhibiting RIPK1 directly and upregulating Trx in sepsis. The purpose of this study is to elucidate the mechanisms of TECs death which caused by sepsis and the mechanism of minocycline to protect TECs from death in sepsis by using bioinformatics, cellular and molecular biology techniques. To set up a novel path for clinical prevention and treatment of TECs from cell death caused by sepsis and optimize the structure of minocycline and develope the novel anti-sepsis drugs for TECs protection. Therefore, it has an important theoretical and clinical significance.