RNAi技术在抑制HBV复制和表达中的应用

发布时间：2018-05-13 11:10

本文选题：RNA干扰(RNAi) + 乙型肝炎病毒(HBV)　；参考：《第一军医大学》2006年博士论文

【摘要】：乙型肝肝炎病毒(HBV)是一种长3.2Kb的DNA病毒，它几乎在整个肝脏可以复制。虽然高活性的乙肝疫苗已问世20多年，但HBV感染仍然是一种危害全球健康的重大疾病。据统计全球约有3.5亿的HBV感染者，而中国又是HBV感染的高发区，约有50％～70％的人群感染过HBV，其中约8％～12％的人群，即超过1亿人口是乙肝表面抗原携带者，每年因急慢性HBV感染致死的人数约有一百万之多。目前，干扰素和腺苷类似物是FDA批准的，仅有的几种抑制HBV复制的药物，但它们的作用效果都很有限。腺苷类似物如lamivudine和adefovir dipivoxil的作用原理是通过抑制HBV逆转录活性，而直接影响病毒复制的，虽然这类药物能高效地清除血清中的HBV-DNA，但不能完全清除体内感染的HBV，因此停止用药后HBV会复发，，并且用药时间的延长会导致HBV病毒突变体的产生。 RNA干扰(RNA interference，RNAi)技术是指内源性或外源性双链RNA(dsRNA)介导的，细胞内mRNA发生特异性降解，并导致靶基因的表达沉默，产生相应的功能表型缺失的一种现象。这一现象属于转录后的基因沉默机制(Posttranscriptional gene silencing，PTGS)。在哺乳动物细胞中RNAi活性主要是通过21～23nt长的small interfering RNAs(siRNA)来实现的。研究表明siRNA已在很多领域显示出对目的基因的清除作用，因此，RNAi也成为治疗HBV感染的一种可选的重要手段。自1998年2月，Fire和Mello两位科学家首次在Nature上发表了：把dsRNA注射入一种线虫(Caenorhabditis elegans)体内，该dsRNA可以诱导基因靶向专一性的基因表达静寂(gene silencing)等研究报告以来，许多研究工作者都先后用RNAi技术，在线虫、果蝇、植物、动物卵细胞和哺乳类细胞中进行了大量研究，
[Abstract]:Hepatitis B virus (HBV) is a long 3.2Kb DNA virus that can be replicated almost throughout the liver. Although the highly active hepatitis B vaccine has been available for more than 20 years, HBV infection is still a major disease that endangers global health. According to statistics, there are about 350 million people living with HBV in the world, and China is also a high incidence area of HBV infection. About 50 percent of the population have been infected with HBV, and about 812 percent of the population, that is, more than 100m people, are carriers of hepatitis B surface antigen. About 1 million people die each year from acute and chronic HBV infections. Currently, interferon and adenosine analogues are approved by FDA, and there are only a few drugs that inhibit HBV replication, but their effects are limited. Adenosine analogues such as lamivudine and adefovir dipivoxil act by inhibiting the reverse transcription activity of HBV, which directly affects viral replication. Although these drugs can effectively eliminate HBV DNA in serum, they can not completely eliminate HBV infection in vivo. Therefore, HBV will recur after stopping treatment, and the prolongation of medication time will lead to the production of HBV virus mutants. RNA interference RNAi technique is an endogenous or exogenous double-stranded RNA-dsRNA-mediated mRNA degradation in cells, resulting in silencing of target gene expression, resulting in the loss of functional phenotypes. This phenomenon belongs to posttranscriptional gene silencing mechanism. RNAi activity in mammalian cells is mainly achieved by 21~23nt long small interfering RN AssiRNAs. Studies have shown that siRNA has been shown to scavenge the target gene in many fields, so siRNA has become an important alternative in the treatment of HBV infection. Since February 1998, when two scientists, Fire and Mello, first published on Nature: injecting dsRNA into a nematode, Caenorhabditis elegant anss, the dsRNA has induced gene targeting to specific gene expression, silent gene silencing, and so on. Many researchers have used RNAi technology to do a lot of research in online insects, fruit flies, plants, animal eggs and mammalian cells.
【学位授予单位】：第一军医大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R346;Q789

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