發(fā)布時(shí)間：2018-02-14 04:26

  本文關(guān)鍵詞： 膽酸 NLRP3炎癥小體 炎癥 代謝綜合征 蛋白翻譯后修飾　出處：《浙江大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：機(jī)體的免疫系統(tǒng)與代謝系統(tǒng)之間的相互作用已經(jīng)成為當(dāng)前免疫學(xué)研究的重要前沿課題,二者的相互作用對(duì)于維持機(jī)體代謝平衡和免疫穩(wěn)態(tài)起著重要的調(diào)節(jié)作用。NLRP3炎癥小體活化引起的機(jī)體炎癥被證實(shí)參與多種炎癥性疾病包括代謝綜合征的病理發(fā)生,尋找其內(nèi)源性調(diào)控分子也成為治療NLRP3相關(guān)疾病的重要突破口。本課題組在前期篩選抑制NLRP3炎癥小體活化的體內(nèi)代謝調(diào)節(jié)物時(shí)發(fā)現(xiàn),膽酸具有廣泛、強(qiáng)力且特異性的NLRP3炎癥小體抑制作用,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。機(jī)制研究發(fā)現(xiàn)膽酸通過(guò)TGR5受體激活PKA激酶進(jìn)而直接將NLRP3 291位點(diǎn)的絲氨酸磷酸化,并導(dǎo)致NLRP3的泛素化。隨后的功能實(shí)驗(yàn)證實(shí)PKA引起的NLRP3蛋白291絲氨酸位點(diǎn)磷酸化和泛素化修飾在抑制NLRP3炎癥小體活化過(guò)程中發(fā)揮重要的作用。進(jìn)一步的小鼠體內(nèi)實(shí)驗(yàn)證實(shí)膽酸可以通過(guò)抑制NLRP3炎癥小體從而改善炎癥性疾病的病理發(fā)生,包括膿毒癥、腹腔炎以及二型糖尿病等。本論文的完成揭示了膽酸抗炎作用的新機(jī)制,為膽酸及其受體作為NLRP3相關(guān)炎癥性疾病及代謝綜合征的治療靶點(diǎn)提供了理論依據(jù)。
[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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R589

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 Takemi Otsuki;Megumi Maeda;Shuko Murakami;Hiroaki Hayashi;Yoshie Miura;Masayasu Kusaka;Takashi Nakano;Kazuya Fukuoka;Takumi Kishimoto;Fuminori Hyodoh;Ayako Ueki;Yasumitsu Nishimura;;Immunological Effects of Silica and Asbestos[J];Cellular & Molecular Immunology;2007年04期

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本文編號(hào)：1509870