本文選題：基于 + 細(xì)胞�。� 參考：《南京大學(xué)》2017年碩士論文

【摘要】：過敏性接觸性皮炎(Allergic ContactDermatitis,ACD)是一種主要由T細(xì)胞介導(dǎo)的遲發(fā)型超敏反應(yīng)。其臨床癥狀主要表現(xiàn)為起皰、水腫和紅斑等,目前通常采用環(huán)孢霉素A和糖皮質(zhì)激素等進(jìn)行治療。盡管這些免疫抑制劑能夠有效地調(diào)節(jié)機(jī)體免疫過程中的過度反應(yīng),緩解疾病癥狀,但是選擇性較差,常出現(xiàn)不良反應(yīng)。因此,尋找更高選擇性地針對(duì)過度活化T細(xì)胞的候選藥物顯得尤為迫切。前期研究發(fā)現(xiàn),粉紅單端胞霉菌(Trichotheciumroseum fungus)發(fā)酵代謝產(chǎn)物中分離純化得到的小分子環(huán)肽RoseotoxinB具有獨(dú)特的免疫抑制功能。因此,我們嘗試在小鼠接觸性皮炎模型中研究Roseotoxin B的免疫抑制活性。在第一章中,我們對(duì)接觸性皮炎和小分子環(huán)肽Roseotoxin B目前的研究進(jìn)展進(jìn)行綜述介紹,闡述了目前接觸性皮炎發(fā)病的影響因素、致病機(jī)理、調(diào)控因素以及常用藥物,同時(shí)也揭示了Roseotoxin B治療免疫性疾病的潛質(zhì)。在第二章中,我們構(gòu)建動(dòng)物模型考察Roseotoxin B對(duì)PC1誘導(dǎo)的接觸性皮炎的治療作用。實(shí)驗(yàn)結(jié)果發(fā)現(xiàn),給予RoseotoxinB的小鼠能明顯緩解耳組織病理變化及耳部厚度,改善接觸性皮炎的發(fā)病程度。之后,我們利用細(xì)胞學(xué)實(shí)驗(yàn)考察了RoseotoxinB對(duì)T淋巴細(xì)胞的影響。實(shí)驗(yàn)結(jié)果顯示,RoseotoxinB不影響T細(xì)胞的活化,但是能顯著抑制活化T細(xì)胞的增殖、炎癥因子的釋放,并且能夠造成活化T細(xì)胞的周期阻滯。以上結(jié)果提示環(huán)肽Roseotoxin B可顯著改善小鼠接觸性皮炎模型,其作用與影響T細(xì)胞密切相關(guān)。在第三章中,我們針對(duì)RoseotoxinB改善小鼠接觸性皮炎展開分子機(jī)制的研究。結(jié)果發(fā)現(xiàn),小分子環(huán)肽RoseotoxinB可通過上調(diào)活化T細(xì)胞的自噬水平來降低炎癥反應(yīng)、阻滯細(xì)胞周期。最后我們又回歸到整體動(dòng)物水平進(jìn)行了驗(yàn)證,發(fā)現(xiàn)Roseotoxin B改善PCl誘發(fā)的小鼠接觸性皮炎是依賴于LC3介導(dǎo)的自噬反應(yīng)的。通過上述研究,我們證明了 RoseotoxinB具有改善PCl誘導(dǎo)的接觸性皮炎的作用,揭示了 RoseotoxinB通過上調(diào)自噬抑制活化T細(xì)胞增殖,發(fā)揮免疫抑制活性的藥理學(xué)新機(jī)制。本研究不僅為通過調(diào)控自噬改善T細(xì)胞介導(dǎo)的免疫性疾病提供了例證,也為臨床上接觸性皮炎的治療提供了新的候選藥物。
[Abstract]:Allergic contact Dermatitis (ACD) is a delayed hypersensitivity reaction mediated by T cells. Its clinical symptoms include blister, edema and erythema, which are usually treated with cyclosporine A and glucocorticoid. Although these immunosuppressants can effectively regulate the overreaction in the immune process and relieve the symptoms of the disease, the selectivity is poor and adverse reactions often occur. Therefore, it is urgent to search for more selective candidate drugs for over-activated T cells. In previous studies, it was found that the small molecular cyclic peptide RoseotoxinB isolated from the metabolites of Trichothecium roseum fungus. had unique immunosuppressive function. Therefore, we try to study the immunosuppressive activity of Roseotoxin B in mouse contact dermatitis model. In the first chapter, we reviewed the current research progress of contact dermatitis and small molecular cyclic peptide Roseotoxin B, and expounded the influencing factors, pathogenesis, regulatory factors and common drugs of contact dermatitis. It also reveals the potential of Roseotoxin B in the treatment of immune diseases. In chapter 2, we established animal models to investigate the therapeutic effect of Roseotoxin B on PC1 induced contact dermatitis. The results showed that RoseotoxinB could alleviate the pathological changes of ear tissue and the thickness of ear and improve the degree of contact dermatitis. After that, we investigated the effect of RoseotoxinB on T lymphocytes by cytological experiments. The results showed that Roseotoxin B did not affect the activation of T cells, but significantly inhibited the proliferation of activated T cells, the release of inflammatory factors, and caused the cycle arrest of activated T cells. These results suggest that cyclopeptide Roseotoxin B can significantly improve the contact dermatitis model in mice, and its effect is closely related to the influence of T cells. In Chapter 3, we investigate the molecular mechanism of RoseotoxinB in improving contact dermatitis in mice. It was found that small molecular cyclic peptide RoseotoxinB could decrease inflammatory response and block cell cycle by upregulating autophagy of activated T cells. Finally, we returned to the whole animal level to verify that the improvement of Roseotoxin B in PCl induced contact dermatitis in mice was dependent on LC3 mediated autophagy. Through the above studies, we proved that RoseotoxinB can improve the contact dermatitis induced by PCl, and revealed a new pharmacological mechanism of RoseotoxinB inhibiting T cell proliferation through upregulation of autophagy and exerting immunosuppressive activity. This study not only provides an example for the improvement of T cell mediated immune diseases by regulating autophagy, but also provides a new candidate for the treatment of contact dermatitis.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R758.22

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1 胡春暉;基于T細(xì)胞自噬調(diào)控的小分子環(huán)肽Roseotoxin B改善接觸性皮炎的機(jī)制研究[D];南京大學(xué);2017年

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本文編號(hào)：1813039