胆酸对NLRP3炎症小体及相关炎症性疾病的调控功能与机制研究

发布时间：2018-02-14 04:26

本文关键词： 胆酸 NLRP3炎症小体炎症代谢综合征蛋白翻译后修饰　出处：《浙江大学》2017年博士论文　论文类型：学位论文

【摘要】：机体的免疫系统与代谢系统之间的相互作用已经成为当前免疫学研究的重要前沿课题,二者的相互作用对于维持机体代谢平衡和免疫稳态起着重要的调节作用。NLRP3炎症小体活化引起的机体炎症被证实参与多种炎症性疾病包括代谢综合征的病理发生,寻找其内源性调控分子也成为治疗NLRP3相关疾病的重要突破口。本课题组在前期筛选抑制NLRP3炎症小体活化的体内代谢调节物时发现,胆酸具有广泛、强力且特异性的NLRP3炎症小体抑制作用,包括pro-caspase-1和pro-IL-1β的切割成熟、IL-1β和IL-18成熟形式的分泌以及ASC speck的形成等。机制研究发现胆酸通过TGR5受体激活PKA激酶进而直接将NLRP3 291位点的丝氨酸磷酸化,并导致NLRP3的泛素化。随后的功能实验证实PKA引起的NLRP3蛋白291丝氨酸位点磷酸化和泛素化修饰在抑制NLRP3炎症小体活化过程中发挥重要的作用。进一步的小鼠体内实验证实胆酸可以通过抑制NLRP3炎症小体从而改善炎症性疾病的病理发生,包括脓毒症、腹腔炎以及二型糖尿病等。本论文的完成揭示了胆酸抗炎作用的新机制,为胆酸及其受体作为NLRP3相关炎症性疾病及代谢综合征的治疗靶点提供了理论依据。
[Abstract]:The interaction between immune system and metabolic system has become an important frontier topic in immunology. The interaction between the two plays an important role in maintaining metabolic balance and immune homeostasis. The inflammation caused by the activation of NLRP3 inflammatory bodies has been proved to be involved in the pathogeny of many inflammatory diseases, including metabolic syndrome. Searching for its endogenous regulatory molecules has also become an important breakthrough in the treatment of NLRP3 related diseases. Our team found that cholic acid has a wide range of metabolic regulators in the early stage when screening the metabolites that inhibit the activation of inflammatory bodies of NLRP3. Strong and specific inhibitory effects of NLRP3 inflammatory bodies, Including the secretion of IL-1 尾 and IL-18 mature forms of pro-caspase-1 and pro-IL-1 尾, and the formation of ASC speck, it was found that cholic acid activates PKA kinase through TGR5 receptor and phosphorylates serine at NLRP3 291 directly. Subsequent functional experiments confirmed that phosphorylation and ubiquitin modification of NLRP3 protein 291 serine site induced by PKA play an important role in inhibiting the activation of NLRP3 inflammatory bodies. To prove that solid cholic acid can improve the pathogenicity of inflammatory diseases by inhibiting the inflammatory bodies of NLRP3. This paper reveals a new mechanism of cholic acid anti-inflammatory effect and provides a theoretical basis for the use of cholic acid and its receptors as targets for the treatment of inflammatory diseases and metabolic syndrome associated with NLRP3.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R589

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