發(fā)布時(shí)間：2018-09-13 11:49

【摘要】：CARASIL是一種直接影響腦小血管的單基因疾病,是由編碼Htr A絲氨酸肽酶/蛋白酶1(HTRA1)的HTRA1基因突變引起。CARASIL在成年早期發(fā)病,多發(fā)生于男性,其確切發(fā)病率尚不清楚。主要臨床表現(xiàn)為缺血性腦卒中或逐步惡化的腦功能、癡呆、早禿和嚴(yán)重腰痛、變形性脊椎病和椎間盤突出等。影像學(xué)特征表現(xiàn)是通過頭部CT掃描和腦磁共振成像觀察到位于基底節(jié)和丘腦的彌漫性白質(zhì)改變、多發(fā)腔隙性腦梗死。在組織病理學(xué)上,CARASIL主要表現(xiàn)為小穿通動(dòng)脈的動(dòng)脈硬化伴隨著內(nèi)膜增厚、血管平滑肌細(xì)胞損失和中膜透明變性。HTRA1基因位于10q26區(qū)域,包含有9個(gè)外顯子,CARASIL相關(guān)的等位基因變異體出現(xiàn)在外顯子1、3、4和6上,共有11個(gè)突變位點(diǎn),包括7個(gè)錯(cuò)義突變、1個(gè)移碼突變、2個(gè)無義突變和1個(gè)缺失突變。HTRA1是一種分泌型絲氨酸蛋白酶,可以促進(jìn)細(xì)胞外基質(zhì)蛋白的變性,也起著重要的生理作用,與關(guān)節(jié)炎、癌癥疾病、家族性缺血性腦小血管病、年齡相關(guān)性黃斑變性和阿爾茨海默氏病等有關(guān)。HTRA1蛋白酶功能喪失導(dǎo)致CARASIL,但確切的機(jī)制尚不完全明確。2007年,我們報(bào)道了國內(nèi)首例CARASIL家系,經(jīng)基因檢測(cè)分析,發(fā)現(xiàn)了在外顯子6上的一個(gè)新的HTRA1基因錯(cuò)義突變:1091TC(點(diǎn)突變)。前期的研究發(fā)現(xiàn),該位點(diǎn)突變的HTRA1基因可以導(dǎo)致HTRA1m RNA及其蛋白的表達(dá)減少,并引起TGF-β1/Smads/CTGF信號(hào)通路的表達(dá)上調(diào)。在本實(shí)驗(yàn)中,我們利用HTRA突變型和野生型基因慢病毒表達(dá)載體感染人腦血管平滑肌細(xì)胞,觀察該細(xì)胞的功能及氧化還原反應(yīng)情況,以此來探討CARASIL的發(fā)病機(jī)制。第一部分HTRA1基因過表達(dá)慢病毒載體構(gòu)建研究目的:構(gòu)建針對(duì)HTRA1基因以及其1091TC突變基因(HTRA1-Mut)的過表達(dá)慢病毒載體。研究方法:利用NCBI Genbank數(shù)據(jù)庫設(shè)計(jì)并構(gòu)建HTRA1基因的引物,利用PCR法釣取并擴(kuò)增野生型和突變型HTRA1基因并酶切慢病毒載體GV287,將HTRA1基因重組入GV287并轉(zhuǎn)化預(yù)先培養(yǎng)好的感受態(tài)細(xì)胞。挑選克隆行PCR初步鑒定HTRA1重組的情況,對(duì)PCR鑒定陽性的細(xì)胞送基因測(cè)序,與Genbank數(shù)據(jù)庫中的HTRA1序列進(jìn)行比對(duì),驗(yàn)證慢病毒載體構(gòu)建成功。將制備好的GV287載體同兩種裝載慢病毒輔助原件的載體抽提后共同轉(zhuǎn)染293T細(xì)胞系,并用western blot進(jìn)行檢測(cè)轉(zhuǎn)入的HTRA1基因表達(dá)情況,熒光法和Elisa法檢測(cè)病毒滴度。結(jié)果:通過設(shè)計(jì)的引物PCR擴(kuò)增得到HTRA1基因以及HTRA1-Mut基因的目的片段,同GV287進(jìn)行酶切后成功轉(zhuǎn)化細(xì)菌感受態(tài)細(xì)胞,PCR鑒定陽性的克隆進(jìn)行測(cè)序和比對(duì)分析顯示與Genbank數(shù)據(jù)庫中的HTRA1基因以及HTRA1-Mut基因序列一致。HTRA1/HTRA1-Mut表達(dá)載體轉(zhuǎn)染293T后,細(xì)胞內(nèi)可觀察到明顯的熒光,測(cè)定病毒滴度為:2E+8TU/ml。結(jié)論:成功構(gòu)建了HTRA1基因及HTRA1-Mut基因真核表達(dá)載體;成功對(duì)HTRA1及HTRA1-Mut慢病毒進(jìn)行了包裝與滴度檢測(cè)。第二部分HTRA1基因慢病毒載體感染血管平滑肌細(xì)胞模型的建立研究目的:對(duì)人腦血管平滑肌細(xì)胞(HBVSMC)進(jìn)行HTRA1及HTRA1-Mut過表達(dá)慢病毒載體感染。研究方法:對(duì)HBVSMC進(jìn)行細(xì)胞培養(yǎng),α-SMA抗體熒光染色進(jìn)行表型鑒定;對(duì)培養(yǎng)后生長良好的HBVSMC進(jìn)行HTRA1及HTRA1-Mut過表達(dá)慢病毒載體感染。結(jié)果:HBVSMC生長狀態(tài)良好,光鏡下細(xì)胞形態(tài)正常,對(duì)細(xì)胞行,α-SMA抗體染色細(xì)胞熒光顯色良好;HTRA1及HTRA1-Mut過表達(dá)慢病毒載體感染后HBVSMC有熒光表達(dá),并且熒光率達(dá)80%以上。結(jié)論:成功培養(yǎng)HBVSMC細(xì)胞系并進(jìn)行了初步鑒定成功;成功建立HTRA1及HTRA1-Mut基因慢病毒載體感染血管平滑肌細(xì)胞模型。第三部分HTRA1基因突變對(duì)人腦血管平滑肌細(xì)胞的增殖、遷移、凋亡的影響研究目的:檢測(cè)HTRA1及HTRA1-Mut基因慢病毒載體轉(zhuǎn)染HBVSMC后,HBVSMC的增殖、遷移及凋亡的變化。研究方法:將HBVSMC分為三組,NC正常的人腦血管平滑肌細(xì)胞組,OE-WT HTRA1野生型病毒感染細(xì)胞組及OE-MU HTRA1突變型病毒感染細(xì)胞組,細(xì)胞培養(yǎng)良好后分別行CCK-8檢測(cè)細(xì)胞增殖,Transwell實(shí)驗(yàn)檢測(cè)細(xì)胞的遷移,細(xì)胞凋亡用流式細(xì)胞術(shù)檢測(cè)。結(jié)果:相比正常的人腦血管平滑肌細(xì)胞(NC),HTRA1野生型病毒感染細(xì)胞(OE-WT)增殖無明顯變化,HTRA1野生型病毒感染細(xì)胞(OE-MU)增殖減緩。與正常的人腦血管平滑肌細(xì)胞(NC)相比,HTRA1野生型病毒感染細(xì)胞(OE-WT)Transwell轉(zhuǎn)移率無明顯差異(P0.05),HTRA1突變型病毒感染細(xì)胞(OE-MU)Transwell轉(zhuǎn)移率降低(P0.05);OE-WT組與OE-MU組相比,OE-MU組的人腦血管平滑肌細(xì)胞的轉(zhuǎn)移率明顯降低(P0.05)。與正常細(xì)胞組(NC)相比,HTRA1野生型病毒感染細(xì)胞(OE-WT)凋亡數(shù)減少(p0.05),而在HTRA1突變型病毒感染細(xì)胞(OE-MU)未見明顯凋亡數(shù)減少(P0.05),與HTRA1野生型病毒感染細(xì)胞(OE-WT)相比,HTRA1突變型病毒感染細(xì)胞(OE-MU)凋亡數(shù)增多(P0.05)。結(jié)論:HTRA1突變型基因感染人腦血管平滑肌細(xì)胞后引起該細(xì)胞增殖能力和遷移活性減弱,并且影響細(xì)胞凋亡。第四部分HTRA1基因?qū)ν蛔冄芷交〖?xì)胞氧化反應(yīng)的影響研究目的:檢測(cè)HTRA1及HTRA1-Mut基因慢病毒載體轉(zhuǎn)染HBVSMC后,HBVSMC內(nèi)氧化應(yīng)激水平的變化。研究方法:HTRA1及HTRA1-Mut基因慢病毒載體轉(zhuǎn)染HBVSMC后,在特定的時(shí)間點(diǎn)收集NC、OE-WT HTRA1及OE-MU HTRA1三組細(xì)胞的總RNA及總蛋白,分別用Real-time PCR和Western Blot的方法檢測(cè)三組細(xì)胞的NOXm RNA及蛋白水平的表達(dá)情況,用DCFH-DA法檢測(cè)三組細(xì)胞內(nèi)的活性氧水平。結(jié)果:從定量PCR結(jié)果可以看出,人腦血管平滑肌細(xì)胞中,OE-MU組NOX4基因表達(dá)豐度是NC組的2.015倍。從Western blot結(jié)果可以看出,在正常的人腦血管平滑肌細(xì)胞中NOX蛋白水平表達(dá)較低,而在慢病毒LV-HRTA1及LV-HRTA1-MUT感染后NOX4蛋白表達(dá)水平增高。在正常的人腦血管平滑肌細(xì)胞中ROS水平表達(dá)較低,而在慢病毒LV-HRTA1及LV-HRTA1-MUT感染后ROS蛋白表達(dá)水平增高,在突變型病毒感染細(xì)胞組表現(xiàn)更為明顯。結(jié)論:1、HTRA1突變型基因感染人腦血管平滑肌細(xì)胞后,細(xì)胞內(nèi)活性氧產(chǎn)量增加,NOX4m RNA水平的表達(dá)正常細(xì)胞升高,但較HTRA1野生型基因無明顯差別;NOX4在蛋白水平表達(dá)較其它兩組均升高。2、HTRA1突變型基因感染的人腦血管平滑肌細(xì)胞出現(xiàn)增殖減少、遷移活力降低以及凋亡增加可能與細(xì)胞內(nèi)的氧化應(yīng)激有關(guān),為進(jìn)一步研究CARASIL發(fā)病機(jī)制奠定基礎(chǔ)。
[Abstract]:CARASIL is a monogenic disease that directly affects the small blood vessels of the brain. It is caused by a mutation in the Htr A serine peptidase/protease 1 (HTRA1) gene. CARASIL occurs in early adulthood, mostly in men, and its exact incidence is not yet known. The main clinical manifestations are ischemic stroke or progressive deterioration of brain function, dementia, early alopecia and premature alopecia. Severe low back pain, deformable spondylopathy, and intervertebral disc herniation. Imaging features include diffuse white matter changes in the basal ganglia and thalamus, and multiple lacunar infarctions. Histopathologically, CARASIL is characterized by arteriosclerosis of small perforating arteries with intimal thickening. Vascular smooth muscle cell loss and clear degeneration of the mesangium. HTRA1 gene is located in the 10q26 region and contains nine exons. CARASIL-related allele variants appear on exons 1, 3, 4 and 6. There are 11 mutations, including 7 missense mutations, 1 shift mutation, 2 nonsense mutations and 1 deletion mutation mutation. HTRA1 is a secretory serine. Acid protease, which can promote the degeneration of extracellular matrix protein, also plays an important physiological role. It is related to arthritis, cancer, familial ischemic cerebellar vascular disease, age-related macular degeneration and Alzheimer's disease. Loss of function of HTRA1 protease leads to CARASIL, but the exact mechanism is not yet clear. A new missense mutation of HTRA1 gene on exon 6, 1091TC (point mutation), was found in the first CARASIL family in China. Previous studies have shown that the mutation of HTRA1 gene can reduce the expression of HTRA1m RNA and its protein, and induce the up-regulation of TGF-beta 1/Smads/CTGF signaling pathway. In this study, we used HTRA mutant and wild-type lentiviral expression vectors to infect human cerebral vascular smooth muscle cells, and observed the function and redox reaction of the cells, so as to explore the pathogenesis of CARASIL. Methods: The primers of HTRA1 gene were designed and constructed using NCBI Genbank database. Wild and mutant HTRA1 genes were harvested and amplified by PCR and the lentiviral vector GV287 was digested. The HTRA1 gene was recombined into GV287 and transformed into pre-cultured competent cells. The recombinant HTRA1 was preliminarily identified by PCR, and the positive cells identified by PCR were sequenced and compared with the HTRA1 sequence in Genbank database to verify the success of the construction of lentiviral vector. Results: The target fragments of HTRA1 gene and HTRA1-Mut gene were amplified by designed primers PCR. After digestion with GV287, the transfected cells were transformed successfully. The positive clones identified by PCR were sequenced and compared with Genbank number. The sequence of HTRA1 gene and HTRA1-Mut gene in the database was identical. After transfection of 293T with HTRA1/HTRA1-Mut expression vector, obvious fluorescence was observed and the viral titer was determined as 2E+8TU/ml. Conclusion: Eukaryotic expression vectors of HTRA1 gene and HTRA1-Mut gene were successfully constructed, and HTRA1 and HTRA1-Mut lentiviruses were successfully packaged and titered. Objective: To establish a model of human cerebral vascular smooth muscle cells (HBVSMC) infected with HTRA1 and HTRA1-Mut lentiviral vectors. Methods: HBVSMC cells were cultured and phenotyped by alpha-SMA antibody fluorescence staining. HBVSMC was infected by lentiviral vector with over-expression of HTRA1 and HTRA1-Mut. Results: HBVSMC grew well, the morphology of cells was normal under light microscope, and the cells stained with anti-alpha-SMA antibody showed good fluorescence staining; HBVSMC with over-expression of HTRA1 and HTRA1-Mut expressed fluorescence, and the fluorescence rate was over 80%. BVSMC cell lines were identified successfully and the model of VSMC infected with HTRA1 and HTRA1-Mut lentiviral vector was established successfully. Part III The effect of HTRA1 gene mutation on proliferation, migration and apoptosis of human VSMC Objective: To detect the effect of HTRA1 and HTRA1-Mut lentiviral vector on HBVSMC transfection. Methods: HBVSMC was divided into three groups: normal NC human cerebral vascular smooth muscle cell group, OE-WT HTRA1 wild type virus infection cell group and OE-MU HTRA1 mutant virus infection cell group. Results: Compared with normal human cerebrovascular smooth muscle cells (NC), the proliferation of HTRA1 wild-type virus-infected cells (OE-WT) was not significantly changed, and the proliferation of HTRA1 wild-type virus-infected cells (OE-MU) was slowed down. Compared with normal human cerebrovascular smooth muscle cells (NC), the Transwell metastasis of HTRA1 wild-type virus-infected cells (OE-WT) was observed. There was no significant difference (P 0.05), but the Transwell metastasis rate of HTRA1 mutant virus-infected cells (OE-MU) was decreased (P 0.05). Compared with OE-MU group, the metastasis rate of human cerebral vascular smooth muscle cells in OE-WT group was significantly decreased (P 0.05). Compared with NC group, the apoptosis of HTRA1 wild type virus-infected cells (OE-WT) was decreased (P 0.05), but the apoptosis rate of HTRA1 protrusion was decreased (P 0.05). There was no significant decrease in the number of apoptosis in OE-MU cells (P 0.05). Compared with OE-WT cells infected by HTRA1, the number of apoptosis in OE-MU cells infected by HTRA1 was increased (P 0.05). Conclusion: The proliferation and migration activity of OE-MU cells infected by HTRA1 mutation gene were decreased, and the migration activity was also decreased. Objective: To detect the changes of oxidative stress in HBVSMC transfected with HTRA1 and HTRA1-Mut lentiviral vectors. Methods: NC and OE were collected at specific time points after HTRA1 and HTRA1-Mut lentiviral vectors were transfected into HBVSMC. The expression of NOXm RNA and protein in three groups of cells was detected by Real-time PCR and Western Blot respectively, and the levels of reactive oxygen species (ROS) in three groups of cells were detected by DCFH-DA method. The expression level of NOX protein in normal human cerebral vascular smooth muscle cells was lower than that in normal human cerebral vascular smooth muscle cells, but the expression level of NOX 4 protein was higher after infection with lentivirus LV-HRTA1 and LV-HRTA1-MUT. The expression of ROS in normal human cerebral vascular smooth muscle cells was lower than that in lentivirus LV-HRTA1-MUT cells. CONCLUSION: 1. The production of reactive oxygen species (ROS) and the expression of NOX4m RNA in human cerebral vascular smooth muscle cells infected with HTRA1 mutant gene increased, but NOX4 was not significantly different from that of HTRA1 wild type gene. Compared with the other two groups, the expression of protein was increased. 2. The proliferation, migration and apoptosis of human cerebral vascular smooth muscle cells infected with HTRA1 mutant gene decreased, which may be related to oxidative stress in cells.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R743

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