本文選題：肺結(jié)核　切入點：網(wǎng)絡(luò)meta分析　出處：《吉林大學》2015年博士論文　論文類型：學位論文

【摘要】：肺結(jié)核（pulmonary tuberculosis）是由結(jié)核分枝桿菌(Mycobacteriumtuberculosis, MTB)感染引起的以侵襲肺部為主的慢性傳染病。目前，肺結(jié)核已經(jīng)成為危害人類公共健康的全球性問題。據(jù)世界衛(wèi)生組織（world healthorganization，WHO）發(fā)布的統(tǒng)計結(jié)果，2010年全球肺結(jié)核新發(fā)病例880萬，約有145萬人死于肺結(jié)核。隨著抗生素的廣泛使用，結(jié)核分枝桿菌的耐藥問題日益嚴重，隨之產(chǎn)生的多重耐藥肺結(jié)核(multidrug resistance tuberculosis, MDR-TB)，甚至廣泛耐藥肺結(jié)核(extensively drug tuberculosis resistant, XDR-TB)更成為了全球結(jié)核病防控的主要威脅。普通的肺結(jié)核服用一線抗結(jié)核藥物，半年左右即可治愈，而耐藥肺結(jié)核的治療周期一般不少于18個月，且所服藥物的副作用較之普通藥物更大，但治療效果卻十分有限。因此，在肺結(jié)核的治療過程中，選擇有效性及安全性俱佳的藥物是耐藥肺結(jié)核治療的關(guān)鍵因素。同時，避開結(jié)核分枝桿菌傳統(tǒng)藥物產(chǎn)生的細菌耐藥性，開發(fā)針對結(jié)核分枝桿菌的有效作用靶點的新型藥物迫在眉睫。結(jié)核分枝桿菌作為結(jié)核病的病原菌，其致病基因成分復雜，在病原菌的進化過程中，基因水平轉(zhuǎn)移(horizontal gene transfer，HGT)是目前結(jié)核分枝桿菌致病的主要推動因素。毒力島(pathogenicity island，PAI)正是來源于大片段DNA的水平轉(zhuǎn)移，位于基因組的特殊區(qū)域，可以將若干功能基因進行有效偶聯(lián)，實現(xiàn)基因功能的互補及整合，是病原菌毒力進化的新方式。近年來隨著高通量生物計算技術(shù)的快速發(fā)展，使病原菌毒力島的高通量篩選成為可能。對結(jié)核分枝桿菌毒力島的泛基因組掃描及功能解析將為我們?nèi)孀⑨屧摬≡闹虏C制奠定分子基礎(chǔ)，對于結(jié)核分枝桿菌的診斷，疫苗及藥物研發(fā)具有至關(guān)重要的作用。 多重耐藥肺結(jié)核較之藥物敏感性肺結(jié)核療程長、費用大且死亡率高。盡管目前有很多對于抗MDR-TB藥物的報道，但還沒有公認的有效藥物用于MDR-TB的治療。本研究通過網(wǎng)絡(luò)meta分析的方法旨在對現(xiàn)有6種抗MDR-TB藥物的有效性及安全性加以評估，尋找有效性和安全性俱佳的抗結(jié)核藥物用于耐藥肺結(jié)核的臨床用藥。本研究使用貝葉斯網(wǎng)絡(luò)meta分析模型，通過6種抗MDR-TB藥物的隨機臨床實驗來評估抗結(jié)核藥物貝寧喹啉、delamanid、利奈唑胺、左氧氟沙星、甲硝唑、莫西沙星的有效性和安全性。本研究系統(tǒng)分析了13項隨機臨床實驗（12篇文獻及ClinicalTrials.gov中的8項隨機臨床實驗），1549例樣本，使用比值比（oddsratios，OR）作為效應量。結(jié)果發(fā)現(xiàn)，6種抗耐藥結(jié)核藥物間的有效性和安全性具有統(tǒng)計學差異，利奈唑胺可能是最為有效的藥物，隨之依次為貝寧喹啉、delamanid、左氧氟沙星、莫西沙星和甲硝唑。 毒力島是一組緊密連鎖且功能上密切相關(guān)的大分子DNA水平轉(zhuǎn)移片段，，它編碼重要的毒力調(diào)控成分，毒力島在病原菌的進化過程中通過基因重組的方式進入宿主菌，從而賦予了宿主菌新的毒力特征，也為病原菌的致病機制提供分子基礎(chǔ)。本研究通過對結(jié)核分枝桿菌基因組任意1000bp片段4-mer核苷酸字符串頻率譜的計算實現(xiàn)結(jié)核分枝桿菌的基因組條形碼可視化注釋，通過異常條形碼區(qū)域歐式距離的計算及篩選，實現(xiàn)對結(jié)核分枝桿菌毒力島的泛基因組掃描，隨后應用Pfam_Scan和Blast2GO功能注釋工具對已篩選得到的毒力島進行功能分析。通過上述分析，我們共篩選得到三個結(jié)核分枝桿菌毒力島區(qū)域，其中即包括了功能已知的毒力島MPI-2和MPI-3，也包括功能未知的毒力島MPI-1。MPI-2和MPI-3這2個毒力島均攜帶編碼PE/PPE家族蛋白的基因，MPI-2編碼so-called Type VIIsecretion systems，功能分析顯示其可作為結(jié)核分枝桿菌早期感染的診斷標志；MPI-3主要參與細胞壁中霉菌酸的合成及與宿主細胞的相互作用，功能分析前世其可作為抗結(jié)核藥物的重要分子靶點；MPI-1的功能目前尚不清楚，但是通過蛋白結(jié)構(gòu)域分析顯示，此毒力島上的基因可能編碼integral membrane nitriteextrusion protein，促進結(jié)核分枝桿菌從有氧生長轉(zhuǎn)變?yōu)榉菑椭瞥至魻顟B(tài)(nonreplicating persistence, NPR)，與結(jié)核分枝桿菌的持續(xù)性感染密切相關(guān)�；蚪M條形碼技術(shù)整合了基因組更多的遺傳信息，具有更高的分辨率。通過對結(jié)核分枝桿菌毒力島的泛基因組掃描及功能解析將為我們?nèi)孀⑨屧摬≡闹虏C制奠定分子基礎(chǔ)，也對結(jié)核分枝桿菌的診斷及疫苗和藥物的研發(fā)起到至關(guān)重要的作用。
[Abstract]:Pulmonary tuberculosis (pulmonary tuberculosis) by Mycobacterium tuberculosis (Mycobacteriumtuberculosis, MTB) infection caused by the invasion of lung infection and chronic diseases. Currently, tuberculosis has become a global problem endangering human public health. According to the WHO (World HealthOrganization WHO) statistics released in 2010, 8 million 800 thousand new cases of pulmonary tuberculosis in the world. About 1 million 450 thousand people died of tuberculosis. With the widespread use of antibiotics, drug resistance of Mycobacterium tuberculosis is becoming increasingly serious, resulting in multiple drug resistant pulmonary tuberculosis (multidrug resistance, tuberculosis, MDR-TB) and extensively drug-resistant tuberculosis (extensively drug tuberculosis resistant, XDR-TB) has become a major threat to the global TB prevention and control of tuberculosis in general. The first-line anti tuberculosis drugs can be cured for about half a year, and a cycle of treatment of drug resistant tuberculosis Like not less than 18 months, and the service is better than the ordinary drug side effects of drugs are more, but the treatment effect is very limited. Therefore, in the treatment of pulmonary tuberculosis, drug efficacy and safety and is a key factor in drug resistant tuberculosis treatment. At the same time, avoid the bacterial resistance of Mycobacterium tuberculosis the traditional drugs, new drug targets for the effective development of Mycobacterium tuberculosis is imminent. Mycobacterium tuberculosis as a pathogen of tuberculosis, the causative gene of complex components, in the process of evolution of pathogenic bacteria, horizontal gene transfer (horizontal gene transfer, HGT) is currently the main push of Mycobacterium tuberculosis pathogenic factors. Pathogenicity island (pathogenicity island, PAI) is derived from the large fragment of DNA horizontal transfer, special area is located in the genome can be effectively coupled several functional genes, gene function The complementary and integration, is a new way of evolution of virulent pathogens. In recent years, with the rapid development of high-throughput biological computing technology, the high-throughput pathogenicity island pathogens to be screened. Analytical scanning and function the pan genome of Mycobacterium tuberculosis virulence island will lay the molecular basis for the pathogenesis of the pathogen was us face annotation, for the diagnosis of Mycobacterium tuberculosis, vaccine and drug development has a crucial role.
Multi drug resistant pulmonary tuberculosis with drug sensitive TB treatment course is long, high cost and high mortality. Although there are many reports for anti MDR-TB drugs, but there is no effective drug accepted for the treatment of MDR-TB. Methods this study through the network meta analysis to the efficacy and safety of the existing 6 kinds of anti MDR-TB drugs to assess, for the safety and efficacy of good anti tuberculosis drugs for drug resistant tuberculosis clinical medication. This study uses Bayesian network meta analysis model, through 6 randomized clinical trials of anti MDR-TB drugs to evaluate the anti TB drugs Benin quinoline, delamanid, linezolid, levofloxacin, metronidazole, effectiveness and safety of moxifloxacin. This study analyzed 13 randomized clinical trials (8 randomized clinical trials of 12 articles in ClinicalTrials.gov), 1549 cases of samples, the odds ratio (o Ddsratios (OR) was used as an effective dose. It was found that the effectiveness and safety of 6 kinds of drug-resistant TB drugs were statistically different. Linezolid is probably the most effective drug, followed by quinoline, delamanid, levofloxacin, moxifloxacin and metronidazole in Benin.
The island is a group of closely linked and function is closely related to the molecular level of DNA fragment encoding it transfer, an important component of the regulation of virulence, pathogenicity island in the evolutionary process of pathogenic bacteria by gene recombination into host bacteria, thus giving the virulence of the new characteristics of the host bacteria, but also provide a molecular basis for the pathogenic mechanism of pathogens bacteria. Based on the calculation of the genome of Mycobacterium tuberculosis 1000bp 4-mer nucleotide fragment of arbitrary string frequency spectrum to achieve the genomic barcode visualization annotation of Mycobacterium tuberculosis, and abnormal screening by calculating the Euclidean distance of the barcode area, realize the pan genome scan of Mycobacterium tuberculosis virulence Island, then analyze the function of the island has been selected the application of Pfam_Scan and Blast2GO functional annotation tools. Through the above analysis, we screened three virulence of Mycobacterium tuberculosis The island area, which include the function of known pathogenicity island MPI-2 and MPI-3, including the unknown function virulent MPI-1.MPI-2 and MPI-3 2 were carrying PE/PPE pathogenicity island encoding protein family genes encoding MPI-2 so-called Type VIIsecretion systems, a functional analysis shows that it can be used as early diagnosis of Mycobacterium tuberculosis infection marker; MPI-3 involved in cell wall synthesis of mycolic acids and host cell interaction, functional analysis of past life which can be used as an important molecular target of anti tuberculosis drugs; the function of MPI-1 is unclear, but through the protein domain analysis showed that this gene may be virulence on the island of integral membrane nitriteextrusion protein encoding, promotion of Mycobacterium tuberculosis coli from aerobic growth into non replicating retention state (nonreplicating persistence, NPR), and the sustainability of Mycobacterium tuberculosis infection. Cut. Genomic barcode technology integrates more genetic information of the genome, with higher resolution. By analyzing the function of scanning and the pan genome of Mycobacterium tuberculosis virulence island for the pathogenic mechanism of the bacteria we fully annotated lay the molecular basis, also research on diagnosis of Mycobacterium tuberculosis and the vaccine and drug to the vital role.

【學位授予單位】：吉林大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R378.911

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