發(fā)布時(shí)間：2018-01-26 17:29

  本文關(guān)鍵詞： 腦膠質(zhì)細(xì)胞瘤 TERT啟動(dòng)子突變 分子標(biāo)志物 預(yù)后分析　出處：《南京醫(yī)科大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：端粒是真核細(xì)胞染色體末端的一段序列,隨著細(xì)胞的分裂而逐漸縮短。端粒酶逆轉(zhuǎn)錄酶(Telomerase reverse transcriptase,TERT)通過(guò)激活端粒酶來(lái)保持端粒的完整,使細(xì)胞獲得無(wú)限增殖能力。TERT在膠質(zhì)瘤細(xì)胞中存在高表達(dá),并與膠質(zhì)瘤的惡性程度密切相關(guān),而正常腦組織中則沒(méi)有TERT的表達(dá)。研究發(fā)現(xiàn)TERT啟動(dòng)子區(qū)域存在兩個(gè)體細(xì)胞突變：C228T和C250T,并導(dǎo)致TERT啟動(dòng)子的轉(zhuǎn)錄活性增加了2-4倍。國(guó)外有報(bào)道發(fā)現(xiàn)TERT啟動(dòng)子突變?cè)谀z質(zhì)母細(xì)胞瘤中頻繁出現(xiàn),并對(duì)預(yù)后產(chǎn)生一定的影響。本研究希望通過(guò)基于中國(guó)人群的大樣本中進(jìn)行TERT啟動(dòng)子突變的檢測(cè),明確其分布規(guī)律和對(duì)于預(yù)后的影響,希望能夠找到一個(gè)具有預(yù)后判斷價(jià)值的分子標(biāo)志物。在本課題的第一部分中,我們對(duì)887例不同級(jí)別、不同組織病理學(xué)亞型的膠質(zhì)瘤樣本進(jìn)行全基因組DNA的提取,通過(guò)巢式PCR擴(kuò)增含有TERT啟動(dòng)子突變的特定區(qū)域,割膠回收純化后進(jìn)行Sanger測(cè)序,通過(guò)比對(duì)分析擴(kuò)增片段中C228T和C250T突變情況,統(tǒng)計(jì)突變率,繪制C228T和C250T突變?cè)诓煌?jí)別,不同組織學(xué)亞型的膠質(zhì)瘤中的分布譜,并揭示其富集規(guī)律。結(jié)果顯示：在887例膠質(zhì)瘤樣本的TERT啟動(dòng)子區(qū)域上,274例被檢測(cè)出含有C228T突變,占到總樣本數(shù)的30.89%,83例含有C250T突變,占到總樣本數(shù)的9.36%。僅有1例樣本同時(shí)存在C228T和C250T雙位點(diǎn)的突變。除10例為純合子突變外,其余所有含有突變點(diǎn)的樣本均為雜合突變。我們按照2007年WHO中樞神經(jīng)系統(tǒng)腫瘤分級(jí)分析了TERT在不同級(jí)別膠質(zhì)瘤中的分布規(guī)律。結(jié)果顯示,在498例WHOⅡ級(jí)膠質(zhì)瘤樣本中,有197例被檢測(cè)出含有TERT突變,突變率為39.56%；在139例WHO Ⅲ級(jí)膠質(zhì)瘤樣本中,有56例被檢測(cè)出含有TERT突變,突變率為40.29%；在250例WHO Ⅳ級(jí)膠質(zhì)瘤樣本中,有104例被檢測(cè)出含有TERT突變,突變率為41.6%。突變率隨著膠質(zhì)瘤級(jí)別的升高略有增加。我們隨后在各組織學(xué)亞型中統(tǒng)計(jì)了TERT啟動(dòng)子的分布規(guī)律：其中少突膠質(zhì)細(xì)胞瘤中TERT啟動(dòng)子突變的富集比例最高,占到75.71%(53/70),星型膠質(zhì)細(xì)胞瘤中TERT啟動(dòng)子的突變頻率最低,僅有10.84%(22/203)。為了更詳細(xì)的描述TERT啟動(dòng)子突變?cè)谀z質(zhì)母細(xì)胞中的分布,我們分別在原發(fā)性膠質(zhì)母細(xì)胞瘤和繼發(fā)性膠質(zhì)母細(xì)胞瘤中分析TERT的突變頻率,結(jié)果顯示44.72%(89/199)的原發(fā)性膠質(zhì)母細(xì)胞瘤含有TERT啟動(dòng)子突變,而只有29.41%(15/51)的繼發(fā)性膠質(zhì)母細(xì)胞瘤含有此突變。通過(guò)上述結(jié)果我們認(rèn)為T(mén)ERT啟動(dòng)子突變?cè)谏偻荒z質(zhì)細(xì)胞瘤中高度富集,突變率隨腫瘤級(jí)別的增加有遞增趨勢(shì),且C228T突變和C250T突變呈明顯的互斥現(xiàn)象。TERT啟動(dòng)子突變?cè)谝灾袊?guó)人群為基礎(chǔ)的膠質(zhì)瘤患者中穩(wěn)定存在,可以作為針對(duì)中國(guó)人群的膠質(zhì)瘤分子標(biāo)志物進(jìn)行預(yù)后分層研究。目前膠質(zhì)瘤治療所面臨的問(wèn)題主要有以下幾個(gè)方面：膠質(zhì)瘤細(xì)胞的侵襲性和浸潤(rùn)性較強(qiáng),這在一定程度上限制了手術(shù)切除的范圍；在化學(xué)治療后很快就會(huì)出現(xiàn)具有抗藥性的細(xì)胞克��；腫瘤細(xì)胞中存在多種致癌信號(hào)通路的激活和基因突變體的相互作用等等。鑒于上述原因,膠質(zhì)瘤,特別是膠質(zhì)母細(xì)胞瘤患者的生存率一直很低,其中位生存期一般不超過(guò)15個(gè)月。然而,仍有不足10%的膠質(zhì)母細(xì)胞瘤患者的壽命可以延長(zhǎng)到三至五年。但是這部分患者生存期延長(zhǎng)的原因和他們本身體質(zhì)以及基因改變之間的原因仍未能明確。有報(bào)道指出：攜帶O6-Methylguanine-DNA methyltransferase (MGMT)啟動(dòng)子甲基化的年輕女性膠質(zhì)瘤患者有機(jī)會(huì)獲得比其他患者更長(zhǎng)的生存期。因此,尋找具有診斷或者預(yù)后意義的特征性分子標(biāo)志物,并進(jìn)行相關(guān)的預(yù)后分層研究對(duì)膠質(zhì)瘤的個(gè)體化治療具有重要的指導(dǎo)意義。因此在本課題的第二部分中,我們針對(duì)不同級(jí)別,不同組織學(xué)亞新的膠質(zhì)瘤進(jìn)行TERT啟動(dòng)子突變的預(yù)后分層研究,并通過(guò)全轉(zhuǎn)錄組測(cè)序數(shù)據(jù)對(duì)膠質(zhì)瘤樣本進(jìn)行TCGA分型注釋,并在Proneural, Neural, Classical, Mesenchymal四個(gè)分子亞型中評(píng)估TERT啟動(dòng)子突變的預(yù)后判斷價(jià)值。結(jié)果顯示：TERT啟動(dòng)子突變組的患者生存期明顯長(zhǎng)于TERT啟動(dòng)子野生組的生存期(P0.05),且C250T突變組的患者生存期長(zhǎng)于C228T突變組的生存期。在WHO Ⅱ級(jí)膠質(zhì)瘤中,TERT啟動(dòng)子突變組的患者生存期的優(yōu)勢(shì)則更加明顯。當(dāng)采用TCGA分型標(biāo)準(zhǔn)對(duì)樣本進(jìn)行分子亞型注釋后我們發(fā)現(xiàn),TERT啟動(dòng)子突變?cè)赑roneural和Mesenchymal兩個(gè)分子亞型中呈現(xiàn)出了明顯的預(yù)后分層,而在Classical和Neural兩個(gè)亞型中的分層并不明顯。據(jù)此我們得出結(jié)論：TERT啟動(dòng)子突變作為判斷膠質(zhì)瘤預(yù)后指標(biāo)的分子標(biāo)志物在TCGA亞型和低級(jí)別膠質(zhì)瘤中的預(yù)測(cè)意義較為明顯,可以作為一個(gè)穩(wěn)定的預(yù)后指標(biāo)為這類膠質(zhì)瘤患者預(yù)后進(jìn)行評(píng)估。近年來(lái)的研究發(fā)現(xiàn)膠質(zhì)瘤在其發(fā)生發(fā)展的過(guò)程中存在著不同的遺傳背景,這些遺傳背景始終貫穿著一個(gè)或幾個(gè)特征性的基因改變。而這些特征性的基因改變也直接或間接的影響著膠質(zhì)瘤的演化和預(yù)后。目前公認(rèn)的是IDH突變是膠質(zhì)瘤發(fā)生基因組改變的早期事件,而TP53突變和1P19Q缺失則分別出現(xiàn)在星形膠質(zhì)細(xì)胞瘤和少突膠質(zhì)細(xì)胞瘤的進(jìn)化過(guò)程中。其中TP53突變更被認(rèn)為是從低級(jí)別星形膠質(zhì)細(xì)胞瘤轉(zhuǎn)化為繼發(fā)性膠質(zhì)母細(xì)胞瘤的過(guò)程中攜帶的遺傳標(biāo)志物。而EGFR擴(kuò)增則是原發(fā)性膠質(zhì)母細(xì)胞瘤的特征性遺傳標(biāo)志物。在第三部分的研究中,我們引入目前已知的與膠質(zhì)瘤預(yù)后密切相關(guān)的分子標(biāo)志物,包括IDH突變、1P19Q缺失、TP53突變,PTEN突變、EGFR擴(kuò)增和MGMT啟動(dòng)子甲基化等,進(jìn)一步分析了TERT突變?cè)谶@些特征性基因變異的情況下對(duì)膠質(zhì)瘤患者的預(yù)后影響。結(jié)果顯示：在1P19Q缺失和IDH1突變的環(huán)境中,TERT啟動(dòng)子突變的預(yù)后優(yōu)勢(shì)更加明顯。此外,在針對(duì)PTEN突變和EGFR擴(kuò)增的聯(lián)合分析中我們發(fā)現(xiàn),只有在不攜帶這兩種分子標(biāo)志物的前提下,TERT啟動(dòng)子突變才可作為預(yù)后較好的分子標(biāo)志物而存在。PTEN突變和EGFR擴(kuò)增對(duì)TERT啟動(dòng)子突變的預(yù)后均存在抑制作用,這種抑制效應(yīng)在TP53突變組中更加明顯。綜上所述,本課題通過(guò)巢式PCR、Sanger測(cè)序、全轉(zhuǎn)錄子測(cè)序、mRNA芯片數(shù)據(jù)、生存預(yù)后統(tǒng)計(jì)等方法,對(duì)膠質(zhì)瘤中TERT啟動(dòng)子突變,TP53突變、IDH突變、1P19Q缺失、PTEN突變和EGFR擴(kuò)增等分子標(biāo)志物進(jìn)行檢測(cè),繪制TERT啟動(dòng)子突變?cè)谀z質(zhì)瘤中的富集譜,綜合評(píng)估了TERT啟動(dòng)子突變作為特征性分子標(biāo)志物在膠質(zhì)瘤中的預(yù)后價(jià)值。這些結(jié)果為后續(xù)深入研究TERT啟動(dòng)子突變影響膠質(zhì)瘤預(yù)后的機(jī)制奠定了基礎(chǔ),也為尋找膠質(zhì)瘤診斷和預(yù)后相關(guān)的分子標(biāo)志物及分子治療的靶點(diǎn)篩選提供了理論參考。
[Abstract]:Telomere is a sequence of end of eukaryotic chromosomes, with cell division and gradually shortened. Telomerase reverse transcriptase (Telomerase reverse, transcriptase, TERT) to keep the integrity of telomeres by activation of telomerase in glioma cells, the cells in the presence of high expression of proliferative ability of.TERT, and with the malignant degree of glioma is closely related however, in normal brain tissue is not the expression of TERT. The study found that the TERT promoter are two somatic mutations: C228T and C250T sub region, and lead to the transcriptional activity of TERT promoter was increased by 2-4 times. The foreign TERT promoter mutation appears frequently in glioblastoma and reported to have a certain impact on the the prognosis of the disease. The author hopes that through a large sample of China population in the TERT promoter mutations based on clearly affect the distribution and the prognosis, hoping to find A prognostic value of molecular markers. In the first part of this paper, we studied 887 cases of different grade glioma samples, extracted from different histopathological subtypes of whole genome DNA, specific regions containing TERT promoter mutations by nested PCR amplification, recovered after purification by Sanger sequencing. Through the comparison and analysis of C228T amplification and C250T mutation fragments, statistical mutation rate, draw C228T and C250T mutation in different levels, the distribution of different histologic subtypes of gliomas in the spectrum, and reveals its enrichment regularity. The results showed that in 887 cases of glioma samples in the promoter region of TERT, 274 cases were detected with the C228T mutation, accounted for the total sample number 30.89%, 83 cases with C250T mutations, mutations accounted for the total number of samples only 1 9.36%. samples C228T and C250T double sites exist at the same time. Except for 10 cases of homozygous mutation, the More than all the sample containing mutations were heterozygous. We analyzed the distribution of TERT in different grades of glioma in 2007 in accordance with the WHO central nervous system tumor grade. The results showed that in 498 cases of WHO grade II glioma samples, 197 cases were detected with the TERT mutation, the mutation rate was 39.56%; in 139 cases of WHO grade III glioma samples, 56 cases were detected with the TERT mutation, the mutation rate was 40.29%; in 250 cases of WHO grade IV glioma samples, 104 cases were detected with the TERT mutation, the mutation rate of 41.6%. mutation rate with gliomas slightly increased. We then the statistical distribution of the TERT promoter in histologic subtypes in various tissues: the enrichment ratio of oligodendroglioma TERT promoter mutation is the highest, accounted for 75.71% (53/70), TERT promoter of glioma in mutation frequency is lowest, only 10.84% (22/203). For a more detailed description of the TERT promoter mutation distribution in glioblastoma cells, we analyze the frequency of TERT mutation in primary glioblastoma and secondary glioblastomas, the results showed that 44.72% (89/199) of primary glioblastoma cells containing TERT promoter the mutation, while only 29.41% (15/51) of the secondary glioblastomas containing this mutation. The above results we concluded that TERT promoter mutations are highly enriched in oligodendroglioma, mutation rate increased with tumor grade have an increasing trend, and the C228T mutation and C250T mutation in.TERT mutual exclusion obvious promoter mutation there are stable in patients with glioma in Chinese population based, can be used for glioma molecular marker for prognosis China population stratification research matter. At present, glioma treatment problems are the following : glioma cell invasion and infiltration is strong, which limits the scope of the surgical resection in a certain extent; in the chemical treatment appear soon after cell clones resistant; there are many oncogenic signaling pathways activated in tumor cells and the mutant gene interaction and so on. In view of the above reasons, glioma in particular, the survival rate of patients with glioblastoma is very low, the median survival period is generally not more than 15 months. However, there is still a shortage of 10% glioblastoma patients life span can be extended to three to five years. But the reason between the causes of the prolonged survival of patients and their health and the change is not clear. The gene has been reported with O6-Methylguanine-DNA methyltransferase (MGMT) promoter in glioma hypermethylation of young female patients have access than other patients Longer survival. Therefore, looking for the characteristic molecular markers with diagnostic or prognostic significance, and has important guiding significance to study the relevant individual prognostic stratification for glioma treatment. In the second part of this paper, we aimed at different levels, different histological sub new glioma research prognostic stratification mutations start TERT, and glioma samples for TCGA type annotation by whole transcriptome sequencing data, and in Proneural, Neural, Classical, TERT promoter mutation prognosis sub judgment to assess the value of Mesenchymal four molecular subtypes. The results showed that TERT promoter survival in patients with mutation group significantly at the TERT promoter wild survival group (P0.05), and the survival of patients with C250T mutation group than the C228T group's survival. Mutations in WHO grade II gliomas, TERT promoter mutation group The survival advantage is more obvious. When using the TCGA classification of molecular subtypes of notes after the samples we found that TERT promoter mutations in Proneural and Mesenchymal two molecular subtypes showed significant prognostic stratification, and stratification in the Classical and Neural two subtypes in which we are not obvious. Conclusion: the TERT promoter mutation as a molecular diagnosis of glioma prognosis predicting markers in TCGA subtypes and low grade gliomas are more obvious, can be used as a prognostic indicator for stability for this kind of patients with glioma prognosis. Recent studies have found that there are different genetic background of glioma in the developing process, the genetic background was always change one or several characteristic genes. Gene change these characteristic also directly or indirectly affect glioma The evolution and prognosis of tumors. The currently accepted IDH mutation is an early event of genomic changes of glioma, and TP53 mutation and 1P19Q deletion were appeared in the process of evolution of astrocytoma and oligodendroglioma. The TP53 mutation is from low-grade astrocytes into tumor genetic markers carrying secondary glioblastomas in. EGFR amplification is a sign of genetic characteristics of primary glioblastoma. In the third part of the study, we introduce the molecule known and glioma is closely related to the prognosis of the markers, including IDH mutation and 1P19Q deletion. TP53 mutation, PTEN mutation, EGFR amplification and MGMT promoter methylation, further analysis of the effect of TERT mutation on the prognosis of patients with glioma in these characteristic gene variations. The results indicated that the deletion of 1P19Q and ID Mutations in the H1 environment, TERT promoter mutations are more obvious advantages of prognosis. In addition, the combined analysis for PTEN mutation and amplification of EGFR we found that only in the premise of not carrying the two kinds of molecular markers, TERT promoter mutations can be used as a molecular marker of good prognosis and.PTEN mutation EGFR amplification of TERT promoter mutations in the prognosis of inhibition are present, the inhibitory effect is more obvious in TP53 mutation group. In summary, this topic by nested PCR, Sanger sequencing, whole transcriptome sequencing, mRNA chip data, after the pre survival statistics of glioma TERT promoter mutation, TP53 mutation. IDH mutation, PTEN mutation and 1P19Q deletion, EGFR amplification and other molecular markers were detected, rendering the mutations of TERT promoter in glioma enrichment spectrum, a comprehensive evaluation of TERT promoter mutations as characteristic molecular markers in Prognostic value of glioma. These results provide a theoretical basis for further research on the mechanism of TERT promoter mutation affecting the prognosis of glioma, and also provide a theoretical reference for finding molecular markers and molecular therapeutic targets of glioma.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R739.41

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8 程文;位志峰;高建平;張征宇;葛京平;景抗震;徐鋒;解鵬;;Effects of Combined siRNA-TR and-TERT on Telomerase Activity and Growth of Bladder Transitional Cell Cancer BIU-87 Cells[J];Journal of Huazhong University of Science and Technology(Medical Sciences);2010年03期

9 梁曉慧;韓璐;李素華;徐新娟;;TERT基因單核苷酸多態(tài)性與新疆維吾爾族人長(zhǎng)壽的關(guān)聯(lián)研究[J];新疆醫(yī)科大學(xué)學(xué)報(bào);2011年10期

10 王菲;常光明;耿鑫;;TERT基因轉(zhuǎn)染的BMSCs對(duì)血管性癡呆大鼠認(rèn)知功能影響的分子機(jī)制研究[J];山東醫(yī)藥;2014年13期

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2 王琰;徐瑞榮;周延峰;劉朝霞;;端粒酶逆轉(zhuǎn)錄酶TERT在獲得性再生障礙性貧血患者中的表達(dá)研究[A];中華中醫(yī)藥學(xué)會(huì)第二屆岐黃論壇——血液病中醫(yī)藥防治分論壇論文集[C];2014年

3 陳晨;張逸杰;徐勇;王燕;黃世勇;陳始明;肖伯奎;陶澤璋;;c-fos和c-jun二聯(lián)體在TERT促進(jìn)多種腫瘤細(xì)胞增殖過(guò)程中的作用研究[A];2010全國(guó)耳鼻咽喉頭頸外科中青年學(xué)術(shù)會(huì)議論文匯編[C];2010年

4 戴文濤;賀凌飛;余日安;陳秉;;鎘對(duì)大鼠肝細(xì)胞端粒酶活性、凋亡和TERT、c-Myc和p53表達(dá)的影響[A];廣東省環(huán)境誘變劑學(xué)會(huì)、廣東省預(yù)防醫(yī)學(xué)會(huì)衛(wèi)生毒理專業(yè)委員會(huì)2010年學(xué)術(shù)會(huì)議資料匯編[C];2010年

5 趙宏賢;王巧稚;徐富翠;余鴻;;DNA去甲基化對(duì)大鼠骨髓間充質(zhì)干細(xì)胞TERT的影響[A];中國(guó)解剖學(xué)會(huì)2011年年會(huì)論文文摘匯編[C];2011年

6 鄭玲玲;蔡琳;;5p15.33(TERT-CLPTM1L)、15q25.1(CHRAN3)基因多態(tài)性與非吸煙者肺癌的關(guān)聯(lián)研究[A];全國(guó)腫瘤流行病學(xué)和腫瘤病因?qū)W學(xué)術(shù)會(huì)議論文集[C];2011年

7 李嬌;屈藝;母得志;;大鼠端粒酶逆轉(zhuǎn)錄酶對(duì)神經(jīng)元缺氧缺血性損傷的保護(hù)作用[A];中華醫(yī)學(xué)會(huì)第十七次全國(guó)兒科學(xué)術(shù)大會(huì)論文匯編（上冊(cè)）[C];2012年

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1 宋勇莉;TERT促耳蝸前體細(xì)胞增殖及其機(jī)制研究[D];第四軍醫(yī)大學(xué);2015年

2 譚卿;尿路上皮腫瘤TERT啟動(dòng)子突變的研究[D];北京協(xié)和醫(yī)學(xué)院;2016年

3 江洋;端粒酶逆轉(zhuǎn)錄酶TERT促進(jìn)人喉癌細(xì)胞Hep-2增殖作用及機(jī)制的研究[D];武漢大學(xué);2013年

4 李瑞;TERT啟動(dòng)子突變?cè)谀z質(zhì)瘤中的分布以及預(yù)后分層研究[D];南京醫(yī)科大學(xué);2016年

5 李小廷;候選SNPs與肺癌的關(guān)聯(lián)分析及作用機(jī)制的研究[D];天津醫(yī)科大學(xué);2015年

6 李曉燕;TERT基因轉(zhuǎn)染骨髓內(nèi)皮祖細(xì)胞移植對(duì)5/6腎切除大鼠腎臟損傷的修復(fù)研究[D];中南大學(xué);2012年

7 楊平勛;TERT在腫瘤細(xì)胞中保護(hù)染色體末端的功能機(jī)制研究[D];中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院;2011年

8 張敏;端粒酶催化亞基TERT在小鼠配子發(fā)生中的表達(dá)檢測(cè)及對(duì)EL-4淋巴瘤細(xì)胞增殖調(diào)節(jié)的研究[D];陜西師范大學(xué);2005年

9 蔡亞南;旋毛蟲(chóng)端粒DNA和TERT基因克隆及端粒酶活性測(cè)定[D];吉林大學(xué);2011年

10 王琰;獲得性再生障礙性貧血患者Shelterin、TERT基因表達(dá)及其與中醫(yī)證型關(guān)系的研究[D];山東中醫(yī)藥大學(xué);2012年

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2 盧保德;廣西地區(qū)人群XRCC4、TERT基因單核苷酸多態(tài)性與膀胱癌易感性的關(guān)系[D];廣西醫(yī)科大學(xué);2016年

3 張佩;TERT端粒酶非依賴機(jī)制與丙烯酰胺誘導(dǎo)的神經(jīng)元損傷[D];武漢科技大學(xué);2014年

4 尋曉潔;TERT基因甲基化、突變及表達(dá)在腦膠質(zhì)瘤患者中的研究[D];西北大學(xué);2015年

5 宋揚(yáng);RNA干擾TERT基因促進(jìn)脊髓修復(fù)的體外實(shí)驗(yàn)研究[D];新疆醫(yī)科大學(xué);2014年

6 宋景春;TERT在5-HT誘導(dǎo)的肺動(dòng)脈平滑肌細(xì)胞增殖過(guò)程中的作用及機(jī)制研究[D];第四軍醫(yī)大學(xué);2004年

7 樊文倩;TERT在小鼠卵母細(xì)胞和原核期胚胎玻璃化冷凍前后表達(dá)變化的研究[D];鄭州大學(xué);2013年

8 梁爽;小鼠TERT啟動(dòng)子的克隆、活性鑒定及其調(diào)控基因的表達(dá)[D];沈陽(yáng)藥科大學(xué);2009年

9 葉田;TERT在人卵巢顆粒細(xì)胞中的表達(dá)及與體外受精—胚胎移植結(jié)局關(guān)系的研究[D];鄭州大學(xué);2013年

10 應(yīng)文群;TERT在膀胱移行細(xì)胞癌中的表達(dá)及意義[D];青島大學(xué);2002年

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