發(fā)布時(shí)間：2018-06-05 16:47

  本文選題：急性肝功能衰竭 + 四氯化碳��； 參考：《河南師范大學(xué)》2016年碩士論文

【摘要】：急性肝功能衰竭(或急性肝衰竭,acute hepatic failure,AHF)是多種誘因引起的、肝臟細(xì)胞受損嚴(yán)重并致使其多種功能發(fā)生障礙的病死率極高和對(duì)人們的健康威脅較大的一種肝臟疾病,常伴隨多種器官衰竭、肝性腦病、血液動(dòng)力學(xué)紊亂和多種代謝疾病等并發(fā)癥,因其發(fā)生機(jī)制復(fù)雜和影響因素多等原因,致使目前對(duì)其發(fā)病機(jī)理的研究雖然較多但仍尚不完全清楚,且仍沒(méi)有發(fā)現(xiàn)對(duì)其有效的防御和治療辦法,目前仍以綜合治療為主,故而一直以來(lái)急性肝衰竭都是臨床醫(yī)學(xué)上最具挑戰(zhàn)的疾病之一。為此,本文成功構(gòu)建了大鼠AHF模型,并通過(guò)檢測(cè)其血清ALT和AST兩種酶活性、計(jì)算其肝系數(shù)和冰凍切片顯微鏡檢檢驗(yàn)建模效果;Rat Genome 230 2.0基因芯片檢測(cè)其基因表達(dá)變化發(fā)現(xiàn)了4819個(gè)AHF相關(guān)基因,IPA分析其相關(guān)基因表達(dá)變化發(fā)現(xiàn),IL-1、IL-6和IL-8等信號(hào)通路信號(hào)傳導(dǎo)活動(dòng)增強(qiáng),TP53、ATM和AMPK等減弱;細(xì)胞存活、增殖和分化等生理活動(dòng)增強(qiáng),T/B淋巴細(xì)胞凋亡減弱;分析AHF發(fā)生機(jī)理相關(guān)基因表達(dá)變化后預(yù)測(cè),通過(guò)IL-1α→IL-1R1→→MAPK8→FOS/JUN和/或TNFα→TNFRSF1A/B→→Caspases途徑在AHF損傷和進(jìn)展階段調(diào)節(jié)細(xì)胞凋亡、炎癥和免疫反應(yīng),炎癥因子通過(guò)NF-κB途徑在進(jìn)展階段調(diào)節(jié)細(xì)胞凋亡,TP53在進(jìn)展階段抑制細(xì)胞凋亡,恢復(fù)階段細(xì)胞凋亡被抑制(此時(shí)Caspase3表達(dá)下調(diào)),進(jìn)展和恢復(fù)階段通過(guò)肝細(xì)胞增殖來(lái)修復(fù)其損傷(PCNA表達(dá)上調(diào)),因此,本文推測(cè),在CCl4誘導(dǎo)的急性肝衰竭中,IL-1R1、TNFRSF1A/B、Caspase3、TP53、PCNA和NF-κB等基因/蛋白起重要作用。本文選擇使用本實(shí)驗(yàn)室所創(chuàng)的液壓轉(zhuǎn)基因技術(shù)(hydrodynamics-based transgene,HDT)對(duì)小鼠AHF進(jìn)行基因治療初探,通過(guò)血清ALT和AST和冰凍切片顯微檢測(cè)鑒定小鼠AHF模型建立成功,通過(guò)不同注射方式條件摸索(液壓轉(zhuǎn)基因注射生理鹽水/空載體質(zhì)粒-生理鹽水溶液與灌胃建模的前后和不同時(shí)間差)發(fā)現(xiàn),灌胃建模后6h,液壓轉(zhuǎn)基因注射空載體質(zhì)粒pEGFP-C1與液壓轉(zhuǎn)基因注射生理鹽水相比,對(duì)小鼠AHF形成的影響結(jié)果無(wú)顯著性差異,從而為AHF的基因治療打下一定基礎(chǔ)。綜上所述,本文進(jìn)一步闡述和分析了AHF的發(fā)生機(jī)理,探索了液壓轉(zhuǎn)基因目的基因進(jìn)入AHF模型體內(nèi)的最佳注射條件,為更進(jìn)一步的研究及其治療奠定基礎(chǔ)。
[Abstract]:Acute hepatic failure (AHF) is caused by many inducements. Often accompanied by multiple organ failure, hepatic encephalopathy, hemodynamic disorders and many metabolic diseases and other complications, because of its complex mechanism and influence factors and other reasons, As a result, although there are many studies on its pathogenesis at present, it is still not fully understood, and no effective defense and treatment methods have been found. At present, comprehensive treatment is still the main treatment. Acute liver failure has always been one of the most challenging diseases in clinical medicine. Therefore, the rat AHF model was successfully constructed, and the activities of serum ALT and AST were detected. The liver coefficient was calculated and the model was examined by frozen section microscope. The gene expression changes of Rat Genome 230 2.0 gene microarray were detected. The expression changes of 4819 AHF related genes were analyzed and the signal pathways such as IL 1, IL 6 6 and IL-8 were found. The signal transduction activity was enhanced, and TP53 / ATM and AMPK were weakened. Cell survival, proliferation, differentiation and other physiological activities enhanced apoptosis of T / B lymphocytes. Apoptosis, inflammation and immune response were regulated by IL-1 偽 IL-1R1 MAPK8 FOS/JUN and / or TNF 偽 TNFRSF1A/B Caspases pathway during AHF injury and progression. Inflammatory factors regulate apoptosis through NF- 魏 B pathway. TP53 inhibits apoptosis at the progressive stage. Apoptosis was inhibited during the recovery phase (the expression of Caspase3 was down-regulated at this time, and the expression of Caspase3 was up-regulated by the proliferation of hepatocytes during the recovery phase. In acute hepatic failure induced by CCl4, IL-1R1 / TNFRSF1 / TNFRSF1 / TNFRSF1 / TNFRSF1 / TNFRSF1 / TNFRSF1 / TNFRSF1 / TNFRSF1 / TP53 / protein play an important role in acute hepatic failure induced by CCl4. In this paper, hydrodynamics-based transgeneic gene therapy was used to treat AHF in mice. Serum ALT, AST and frozen section microanalysis were used to identify the successful establishment of mouse AHF model. It was found that different injection conditions (hydraulic transgenic injection of normal saline / no-load granulus-saline solution and the difference of time before and after gastric perfusion), There was no significant difference in the effect of hydraulic transgenic injection of no-load body mass pEGFP-C1 and hydraulic transgenic injection of normal saline on the formation of AHF in mice at 6 h after gastric perfusion, which laid a foundation for the gene therapy of AHF. To sum up, the mechanism of AHF was further expounded and analyzed, and the optimal injection conditions of hydraulic transgenic gene into AHF model were explored, which laid a foundation for further research and treatment.
【學(xué)位授予單位】：河南師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R575.3

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