本文選題：甲型流感病毒　切入點(diǎn)：miR-302c　出處：《武漢大學(xué)》2016年博士論文

【摘要】：MicroRNAs (miRNAs)是存在于真核細(xì)胞內(nèi)的18-24個(gè)核苷酸長度的RNA分子。在動(dòng)物中,單鏈miRNA結(jié)合到靶基因]mRNA的3’非翻譯區(qū)抑制mRNA的翻譯或?qū)е耺RNA的降解。近年來各種研究表明,miRNA在流感病毒的復(fù)制和機(jī)體抗病毒免疫中起作用。盡管有microRNA在流感病毒感染和免疫過程中起作用,關(guān)于miR-302c和病毒以及先天免疫系統(tǒng)之間的關(guān)系尚未被闡明。在我們的研究中,我們探索了miR-302家族在病毒的復(fù)制中的功能,發(fā)現(xiàn)miR-302家族中的miR-302c在病毒的復(fù)制中起關(guān)鍵作用。我們還進(jìn)一步研究了miR-302c與miR-520e的關(guān)系,盡管有研究指出miR-520e在肝癌細(xì)胞中通過靶向NIK發(fā)揮其功能,但在我們的研究中發(fā)現(xiàn),在A549細(xì)胞中]miR-520e并不能通過靶向NIK 3'UTR序列來增強(qiáng)病毒的復(fù)制。因此我們推測,在病毒感染過程中,不同的病毒調(diào)節(jié)不同miRNA的表達(dá)來調(diào)控NIK的表達(dá)與干擾素的誘導(dǎo)。NF-κB誘導(dǎo)激酶(NIK)也被稱為MP3K14,是p100加工生成p52所必需的蛋白激酶,也是NF-κB非經(jīng)典通路的重要組成部分。最近的一些研究證實(shí)了NIK在先天免疫和炎癥反應(yīng)中的作用。在我們的研究中發(fā)現(xiàn),miR-302c影響了p65和p50的入核,而對ReIB和p52的入核沒有影響。我們的研究結(jié)果與先前的報(bào)道一致,即NIK能參與調(diào)控經(jīng)典NF-κB通路,雖然其確切的調(diào)控機(jī)制仍有待繼續(xù)研究。近年來,大量的研究已經(jīng)揭示了病毒誘發(fā)Ⅰ型干擾素信號通路的機(jī)制。盡管我們對流感病毒激活天然免疫反應(yīng)的機(jī)制已經(jīng)有很多了解,但是對于microRNA和流感病毒誘導(dǎo)的天然免疫之間的關(guān)系仍然不甚清楚。在我們的研究中,我們觀察到流感病毒通過抑制miR-302c誘導(dǎo)了IFN-β的表達(dá)。我們的數(shù)據(jù)提供了流感病毒激活Ⅰ型干擾素的一種新的機(jī)制。總之,在本論文的研究中,我們證明了之前未被人所知的流感病毒調(diào)節(jié)干擾素β表達(dá)的機(jī)制。我們發(fā)現(xiàn)流感病毒能夠抑制miR-302c表達(dá),從而誘導(dǎo)干擾素β信號通路。我們的研究還證明miR-30302c可以抑制NIK的表達(dá),并通過靶向NIK阻止NF-κB的入核,從而導(dǎo)致對IFN-β及下游信號通路的抑制。我們的結(jié)果揭示了在流感病毒感染中miR-302c扮演的新角色,也為流感病毒的感染提供了一個(gè)潛在的治療策略。
[Abstract]:MicroRNAs is an 18-24 nucleotide length RNA molecule found in eukaryotic cells. Single strand miRNA binds to target gene] the 3'untranslated region of mRNA inhibits the translation of mRNA or leads to the degradation of mRNA. Recent studies have shown that miRNAs play a role in influenza virus replication and body antiviral immunity, despite the presence of microRNA in influenza viruses. Infection and immune processes play a role, The relationship between miR-302c and viruses and innate immune systems has not been clarified. In our study, we explored the role of the miR-302 family in viral replication. We also further studied the relationship between miR-302c and miR-520e. Although some studies have shown that miR-520e can function through targeted NIK in hepatoma cells, we have found that. In A549 cells, miR-520e does not enhance the replication of the virus by targeting the NIK 3'UTR sequence. Different viruses regulate the expression of different miRNA to regulate the expression of NIK and interferon induced. NF- 魏 B induced kinase NIKK, also known as MP3K14, is the protein kinase necessary for p100 to produce p52. It is also an important part of the NF- 魏 B nonclassical pathway. Some recent studies have confirmed the role of NIK in innate immune and inflammatory response. In our study, we found that miR-302c affected the entry of p65 and p50. Our results are consistent with previous reports that NIK is involved in regulating the classical NF- 魏 B pathway, although its exact regulatory mechanism remains to be further studied in recent years. A great deal of research has revealed the mechanism of interferon type I signaling pathway induced by viruses, although we already know a lot about the mechanism of influenza virus activating innate immune response. But the relationship between microRNA and influenza virus-induced innate immunity remains unclear. We have observed that influenza virus induces IFN- 尾 expression by inhibiting miR-302c. Our data provide a new mechanism for influenza virus to activate interferon type 1. We have demonstrated the previously unknown mechanism by which influenza viruses regulate the expression of interferon beta. We have found that influenza viruses can inhibit the expression of miR-302c and thus induce the signaling pathway of interferon beta. Our study also shows that miR-30302c can inhibit the expression of NIK. The inhibition of IFN- 尾 and its downstream signaling pathway by targeting NIK may lead to the inhibition of NF- 魏 B. our results reveal that miR-302c plays a new role in influenza virus infection and provides a potential therapeutic strategy for influenza virus infection.
【學(xué)位授予單位】：武漢大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R392

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