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  本文選題：脊髓損傷　切入點(diǎn)：炎癥反應(yīng)　出處：《暨南大學(xué)》2017年博士論文

【摘要】：目的:近年來,越來越多的證據(jù)表明轉(zhuǎn)錄后的調(diào)控在機(jī)體功能發(fā)揮過程中發(fā)揮極其重要的作用。miRNA作為重要的表觀遺傳學(xué)內(nèi)容受到越來越多的關(guān)注。目前與脊髓損傷(SCI)相關(guān)的miRNA研究大多數(shù)停留在生物信息學(xué)分析層面上,缺乏直接的生物學(xué)證據(jù)。我們擬在前期研究基礎(chǔ)上,篩選與SCI炎癥反應(yīng)密切相關(guān)的miRNA,利用SCI動物模型以及臨床樣本探索miRNA在SCI炎癥反應(yīng)中的主要作用及其機(jī)制。材料與方法:利用SCI動物模型篩選目標(biāo)miRNA,然后利用動物模型和臨床SCI患者樣本驗(yàn)證目標(biāo)miRNA通過調(diào)控其靶基因參與SCI炎癥反應(yīng)并探索該過程的具體機(jī)理。同時檢測分析SCI患者血液樣本目標(biāo)miRNA水平與SCI風(fēng)險的相關(guān)性。結(jié)果:通過動物模型篩選發(fā)現(xiàn)miR-146a表達(dá)量在SCI后發(fā)生顯著變化(P0.05)。發(fā)現(xiàn)miR-146a在SCI后3、7天表達(dá)量顯著上調(diào)。炎癥因子水平在SCI術(shù)后第1天顯著上升,但在術(shù)后第3、7天,相對下降(P0.05)。形態(tài)學(xué)檢測也發(fā)現(xiàn)在SCI術(shù)后損傷部位出現(xiàn)炎性細(xì)胞浸潤。尾靜脈注射miR-146a抑制劑,其靶基因IRAK1和TRAF6以及下游炎癥因子的表達(dá)量顯著升高(P0.05),炎癥反應(yīng)程度上升導(dǎo)致SCI恢復(fù)緩慢;反之,尾靜脈注射miR-146a mimics則能夠抑制其靶基因IRAK1和TRAF6以及下游炎癥因子的表達(dá)量(P0.05),有利于SCI恢復(fù);此外,實(shí)驗(yàn)還證實(shí)miR-146a能夠顯著抑制含有IRAK1和TRAF6基因3’UTR區(qū)熒光素酶載體的表達(dá)(P0.05)。SCI患者血液樣本中miR-146a以及炎癥因子表達(dá)規(guī)律與動物模型一致。結(jié)論:利用動物模型驗(yàn)證miR-146a在SCI后上調(diào)表達(dá)存在時間滯后性,首次提出miR-146a可能靶向下調(diào)IRAK1和TRAF6基因表達(dá),同時又受到炎癥因子的反饋調(diào)節(jié),從而形成一個調(diào)控炎癥反應(yīng)的反饋調(diào)節(jié)機(jī)制,在SCI恢復(fù)過程發(fā)揮積極作用。miR-146a mimics可以降低炎癥反應(yīng),一定程度上更好的促進(jìn)SCI恢復(fù),為SCI臨床診療提供潛在治療策略與治療靶點(diǎn)。
[Abstract]:Objective: in recent years, more and more evidence that post transcriptional regulation plays an extremely important role in the process of.MiRNA as an important content of epigenetics has attracted more and more attention in the body function. At present with spinal cord injury (SCI) of miRNA related research most remain in the bioinformatics analysis level, the lack of direct biological evidence. We plan on the basis of former research, closely related to the miRNA screening and SCI inflammation, SCI animal models and clinical samples to explore the main role of miRNA in SCI in the inflammatory reaction and mechanism. Material and methods: the animal model of target miRNA by SCI screening, the specific mechanism and using animal models and clinical samples of patients with SCI verify that the target miRNA through the regulation of its target genes involved in the inflammatory reaction of SCI and explore the process. At the same time detection and analysis of blood samples of patients with SCI miRNA level target The correlation with the risk of SCI. Results: the animal models were found the expression of miR-146a was changed after SCI (P0.05). MiR-146a was found in the expression of 3,7 was up-regulated after SCI days. Significantly increased the level of inflammatory factors in the first day after SCI, but in 3,7 days after operation, the relative decline (P0.05). Morphological detection is also found in SCI after injury site of inflammatory cell infiltration. Intravenous injection of miR-146a inhibitor and its target gene IRAK1 and TRAF6 and the expression of inflammatory cytokines were significantly increased (P0.05), the degree of inflammatory reaction led to the rise in SCI recovery was slow; on the other hand, intravenous injection of miR-146a mimics can inhibit the target gene IRAK1 and TRAF6 and the expression of inflammatory cytokines content (P0.05), is conducive to the recovery of SCI; in addition, the experiment also confirmed the expression of miR-146a can inhibit the TRAF6 gene containing IRAK1 and 3 'UTR (P0.05).S luciferase vector Blood samples of patients with CI in miR-146a and the expression of inflammatory factors and rules consistent. Conclusion: the animal model using animal models to verify the miR-146a after SCI expression exists time lag, first proposed miR-146a may be targeted down-regulation of IRAK1 and TRAF6 gene expression, but also by the feedback regulation of inflammatory cytokines, thereby forming a regulation of inflammatory reaction a feedback regulation mechanism, play a positive role in SCI recovery process of.MiR-146a mimics can reduce the inflammatory response, to a certain extent, promote the recovery of SCI, and provide potential therapeutic target therapeutic strategy for clinical diagnosis and treatment of SCI.

【學(xué)位授予單位】：暨南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R651.2

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本文編號：1713979