本文選題：CPA1 + 特發(fā)性慢性胰腺炎��； 參考：《第二軍醫(yī)大學(xué)》2017年博士論文

【摘要】：第一部分中國漢族人群中CPA1功能性突變與特發(fā)性慢性胰腺炎關(guān)聯(lián)的鑒定研究研究背景和目的慢性胰腺炎(chronic pancreatitis,CP)是一種胰腺組織進(jìn)行性炎癥病變,反復(fù)發(fā)作,病程長,嚴(yán)重影響患者的生活質(zhì)量。目前,對慢性胰腺炎發(fā)病機(jī)制比較公認(rèn)的觀點(diǎn)是,遺傳因素、環(huán)境因素及兩者的相互作用共同參與了慢性胰腺炎的發(fā)生發(fā)展。在過去的20年間,隨著分子遺傳學(xué)研究的逐步深入,遺傳因素在慢性胰腺炎發(fā)病機(jī)制中占據(jù)了愈發(fā)重要的位置,發(fā)現(xiàn)陽離子胰蛋白酶原基因、陰離子胰蛋白酶原基因、囊性纖維化跨膜轉(zhuǎn)導(dǎo)調(diào)節(jié)因子基因、Kazal 1型絲氨酸蛋白酶抑制劑基因、糜蛋白酶原C基因等在慢性胰腺炎發(fā)病或保護(hù)機(jī)制起重要作用。2013年,來自德國的一項(xiàng)研究報(bào)道了CPA1功能性突變與非酒精性慢性胰腺炎的發(fā)病相關(guān),同時(shí)來自歐洲其他地區(qū)的實(shí)驗(yàn)數(shù)據(jù)以及亞洲的兩個(gè)小樣本研究數(shù)據(jù)(日本、印度)均支持這一結(jié)果。然而,為了證實(shí)某一致病基因確與疾病發(fā)生有關(guān),通常需要進(jìn)行獨(dú)立的、不同人種的重復(fù)實(shí)驗(yàn)。特別是考慮到上述研究中CPA1功能性突變在不同人種間的發(fā)生及分布情況存在很大差異,亞洲人群僅有兩個(gè)小樣本的研究數(shù)據(jù),以及中國人群慢性胰腺炎易感基因和位點(diǎn)可能有別于歐洲人種的情況,進(jìn)行獨(dú)立的、大樣本的中國人群CPA1功能性突變鑒定研究是非常必要的。本研究的目的是探究中國漢族人群中CPA1功能性突變與特發(fā)性慢性胰腺炎的關(guān)聯(lián),進(jìn)一步充實(shí)中國慢性胰腺炎患者的遺傳特征數(shù)據(jù),為慢性胰腺炎的精準(zhǔn)醫(yī)療打下基礎(chǔ)。研究方法本實(shí)驗(yàn)納入了1112名中國漢族特發(fā)性慢性胰腺炎患者以及1580名漢族對照人群,采用目標(biāo)區(qū)域二代測序的方法對其進(jìn)行CPA1全外顯子以及外顯子/內(nèi)含子交界處序列的測序研究,并利用Sanger測序法對發(fā)現(xiàn)的CPA1突變進(jìn)行驗(yàn)證。對新發(fā)現(xiàn)的CPA1突變,進(jìn)行CPA1酶活性及分泌情況的功能研究。研究結(jié)果1、本實(shí)驗(yàn)在中國漢族特發(fā)性慢性胰腺炎患者及漢族對照人群中共發(fā)現(xiàn)18個(gè)CPA1罕見突變,其中11個(gè)突變?yōu)槭状螆?bào)道。2、經(jīng)過功能研究分析,證實(shí)有五個(gè)突變?yōu)楣δ苁軗p性突變,分別是p.Glu100Lys,p.Arg240Gln,p.Gly225Ser,p.His306Tyr,p.Glu380Lys。3、在中國漢族人群中,無論是CPA1罕見突變(患者:20/1112(1.8%)vs.對照:24/1580(1.52%);P=0.573),還是CPA1功能受損性罕見突變(患者:3/1112(0.27%)vs.對照:2/1580(0.13%);P=0.410),均與特發(fā)性慢性胰腺炎的發(fā)生無關(guān)。結(jié)論1、本試驗(yàn)首次重復(fù)研究了CPA1功能突變與特發(fā)性慢性胰腺炎的關(guān)系,是目前樣本量最大的、單一人種的針對CPA1編碼序列及CPA1外顯子/內(nèi)含子交界處序列的測序研究。2、本研究首次報(bào)道了中國漢族人群中CPA1功能性突變與特發(fā)性慢性胰腺炎無顯著關(guān)聯(lián)。此結(jié)論與歐洲數(shù)據(jù)以及亞洲小樣本研究數(shù)據(jù)不一致,這可能是由于人種遺傳因素特異性所致。3、CPA1功能性突變與慢性胰腺炎的關(guān)聯(lián)性在不同人種間存在差異,進(jìn)一步證明了探究本國人群遺傳因素具有重要意義。第二部分SPINK1基因外顯子區(qū)域突變對前體m RNA剪接影響的功能研究研究背景和目的胰腺分泌胰蛋白酶抑制劑基因(pancreatic secretory trypsin inhibitor,SPINK1)是研究最早、最廣泛的慢性胰腺炎易感基因之一,SPINK1的功能喪失性突變在慢性胰腺炎的發(fā)病過程中起重要作用。目前已報(bào)道了32個(gè)SPINK1外顯子區(qū)域突變,其致病機(jī)理研究主要集中于錯(cuò)義突變是否影響了蛋白功能。有研究指出基因外顯子區(qū)域突變可以通過產(chǎn)生新的剪接位點(diǎn),或通過改變與剪接發(fā)生密切相關(guān)的多種順勢作用元件,如剪接增強(qiáng)子、剪接沉默子等,影響前體m RNA剪接功能。同時(shí),越來越多的研究報(bào)道包括同義突變在內(nèi)的外顯子區(qū)域突變可通過影響前體m RNA剪接的方式增加患病風(fēng)險(xiǎn),更有研究預(yù)測,在分布于外顯子末端的致病SNPs突變中,有20-45%的突變可能影響剪接功能。此外,minigene模型是常用的分析基因突變對前體m RNA剪接影響的模型。但minigene舍棄了基因的部分內(nèi)含子或外顯子區(qū)域,可能因此掩蓋了遠(yuǎn)端內(nèi)含子、外顯子對待研究區(qū)域剪接的影響,或改變m RNA二級(jí)結(jié)構(gòu),降低其穩(wěn)定性。本研究的主要目的是使用SPINK1全長基因研究模型,探究SPINK1外顯子區(qū)域突變是否對前體m RNA剪接產(chǎn)生影響,進(jìn)一步鑒定SPINK1外顯子區(qū)域突變的致病性,明確疾病易感突變的致病機(jī)理。同時(shí),通過對比SPINK1全長基因研究模型與SPINK1 minigene研究模型的實(shí)驗(yàn)結(jié)果,進(jìn)一步探討minigene模型給研究結(jié)果帶來的可能偏差。研究方法本課題針對已報(bào)道的32個(gè)SPINK1外顯子區(qū)域突變進(jìn)行研究。構(gòu)建野生型及突變型SPINK1全長基因及minigene載體質(zhì)粒,轉(zhuǎn)染HEK293T細(xì)胞,通過RT-PCR方法研究突變對基因轉(zhuǎn)錄本的影響,并用一代測序檢測轉(zhuǎn)錄本序列;通過Q-PCR的方法研究突變對m RNA相對表達(dá)量的影響。利用Alamut軟件對SPINK1外顯子突變進(jìn)行影響剪接功能的預(yù)測分析。研究結(jié)果1、RT-PCR結(jié)果顯示SPINK1外顯子突變未導(dǎo)致異常轉(zhuǎn)錄本產(chǎn)生。2、Q-PCR結(jié)果顯示SPINK1突變c.27del C(70.5±9.8,P=0.0092)、c.29GA(80.0±4.4,P=0.0029)、c.98_99ins A(71.9±1.9,P=0.0015)、c.190AG(82.2±4.1,P=0.0170)、c.199CT(77.1±10.1,P=0.0070)、c.203AG(87.4±7.0,P=0.0365)可致SPINK1 m RNA相對表達(dá)量降低。3、c.27del C、c.98_99ins A產(chǎn)生提前終止密碼子,NMD抑制劑放線菌酮作用4小時(shí)后,可致攜帶c.27del C突變的m RNA表達(dá)量回升(126.5±2.2,P=0.0023),對c.98_99ins A無影響(107.2±18.4,P=0.3606)。4、Alamut軟件預(yù)測有7個(gè)突變可能對原有剪接位點(diǎn)產(chǎn)生影響,c.190AG等10個(gè)突變可能產(chǎn)生新的剪接位點(diǎn);預(yù)測c.199CT、c.98_99ins A等12個(gè)突變可能降低ESEs活性,有8個(gè)突變可能增強(qiáng)ESEs活性。5、對比SPINK1全長基因模型與SPINK1 minigene模型的研究結(jié)果發(fā)現(xiàn),兩種模型的RT-PCR結(jié)果相似,均可以顯示c.194+2TC突變導(dǎo)致的SPINK1異常轉(zhuǎn)錄本,且外顯子其它突變對SPINK1轉(zhuǎn)錄本并無影響。但Q-PCR結(jié)果有所不同:minigene模型的研究顯示c.110AG(64.1±2.0,P=0.001)、c.137TA(131.1±7.9,P=0.0211)、c.194GA(44.5±6.4,P=0.0044)可影響m RNA的表達(dá)量,而全長基因模型研究未提示突變改變m RNA表達(dá)量;c.190AG在兩種模型中的研究結(jié)果相反,全長基因模型研究顯示該突變可降低SPINK1 m RNA的相對表達(dá)量,而在minigene模型的研究中,該突變增加m RNA的相對表達(dá)量(121.4±2.0,P=0.0030)。結(jié)論1、本研究進(jìn)一步鑒定了SPINK1外顯子區(qū)域突變的致病性,明確了疾病易感突變的致病機(jī)理。2、常用剪接分析模型minigene存在一定缺陷,建議使用全長基因模型進(jìn)行研究分析。
[Abstract]:The first part of the study of the association between CPA1 functional mutation and idiopathic chronic pancreatitis in Chinese Han population, background and objective chronic pancreatitis (chronic pancreatitis, CP) is a progressive inflammatory disease of the pancreatic tissue, recurrent attacks, long course of disease, and serious influence on the quality of life of the patients. It is generally accepted that genetic factors, environmental factors, and their interaction are involved in the development of chronic pancreatitis. In the past 20 years, with the gradual deepening of molecular genetic research, genetic factors have occupied a more important position in the pathogenesis of chronic pancreatitis, and the discovery of the cationic trypsinogen gene, The anionic trypsinogen gene, the cystic fibrosis transmembrane transduction regulator gene, the Kazal 1 serine protease inhibitor gene, and the chymotrypsinogen C gene play an important role in the pathogenesis or protection of chronic pancreatitis,.2013 years. A study from Germany reported that the CPA1 functional mutation and non-alcoholic chronic pancreatitis were reported. Experimental data from other regions of Europe, as well as two small sample data in Asia (Japan, India), support this result. However, in order to confirm that a pathogenic gene is associated with the disease, an independent, different race repeat experiment is usually needed. Especially considering the CPA1 function in the above study. There are great differences in the occurrence and distribution of sexual mutation among different species. There are only two small sample data in Asian population, and the susceptibility genes and loci of chronic pancreatitis in Chinese population may be different from those of European ethnicity. It is necessary to identify the functional mutation of CPA1 in large samples of Chinese people. The purpose of this study was to explore the association of CPA1 functional mutations in Chinese Han population with idiopathic chronic pancreatitis and to further enrich the genetic data of patients with chronic pancreatitis in China, and to lay the foundation for the precise medical treatment of chronic pancreatitis. The study included 1112 patients with chronic chronic pancreatitis in Han Chinese. The sequence of CPA1 total exon and exon / intron junction sequence of 1580 Han control population was sequenced by two generation of target region, and the CPA1 mutation was verified by Sanger sequencing. The function of the CPA1 enzyme activity and secretion of the newly discovered CPA1 mutation was studied. 1, in this experiment, 18 rare CPA1 mutations were found in Chinese Han idiopathic chronic pancreatitis and Han control population, of which 11 mutations were first reported.2. After functional analysis, five mutations were identified as p.Glu100Lys, p.Arg240Gln, p.Gly225Ser, p.His306Tyr, p.Glu380Lys.3, respectively, in China. In the Han population, whether a rare CPA1 mutation (patients: 20/1112 (1.8%) vs. control: 24/1580 (1.52%), P=0.573), or a rare mutation of CPA1 function (patients: 3/1112 (0.27%) vs. control: 2/1580 (0.13%); P=0.410), is not related to the occurrence of idiopathic chronic pancreatitis. Conclusion 1, this trial repeated the first repeated study of CPA1 function mutation and idiopathic The relationship of chronic pancreatitis is the largest sample size at present. The sequence of CPA1 coding sequence and CPA1 exon / intron junction sequence of single human race was sequenced.2. This study was the first to report that there was no significant association between CPA1 functional mutation and idiopathic chronic pancreatitis in Chinese Han population. This conclusion is with European data and Asian samples. The data of this study are inconsistent, which may be due to the genetic factor specificity of.3, and the correlation between CPA1 functional mutation and chronic pancreatitis is different between different people, and further proves the significance of exploring the genetic factors of the population in the country. The second part of the SPINK1 gene exon mutation affects the splicing of the precursor m RNA Functional research background and objective pancreatic secretory trypsin inhibitor (SPINK1) is one of the earliest and most extensive chronic pancreatitis susceptible genes. The loss of function of SPINK1 plays an important role in the pathogenesis of chronic pancreatitis. There are 32 reports of SPINK1 outside of the pathogenesis of chronic pancreatitis. It is pointed out that the mutation of the exon region can be produced by producing new splice sites, or by changing a variety of homeopathic elements closely related to splicing, such as splicing enhancer, splicing silencer, etc., affecting the precursor m RNA At the same time, more and more studies have reported that the exons region mutation, including synonymous mutations, can increase the risk of the disease by affecting the m RNA splicing of the precursor, and more research predicts that the mutation of the 20-45% can affect the splicing function in the pathogenetic SNPs mutation distributed at the exon end of the exons. Furthermore, the minigene model is commonly used. An analysis of the effects of gene mutation on the splicing of the precursor m RNA. But minigene abandons the partial intron or exons of the gene, which may mask the distal intron, the exons treat the study area splicing, or change the m RNA two structure to reduce its stability. The main purpose of this study is to use the SPINK1 full length gene. To investigate whether the mutation of the SPINK1 exon region affects the splicing of the precursor m RNA, further identifying the pathogenicity of the mutation in the exon of SPINK1, and clarification of the pathogenicity of the susceptibility mutation of the disease. At the same time, by comparing the experimental results of the SPINK1 full-length gene research model with the SPINK1 minigene model, the minigene is further explored in minigene. The possible deviation of the model to the results of the study. The research method is aimed at 32 reported mutations in the SPINK1 exons. To construct wild and mutant SPINK1 full length gene and minigene vector plasmid, transfect HEK293T cells, and study the effect of mutation on the gene transcript by RT-PCR method, and use one generation sequencing test. Transcriptional sequence; study the effect of mutation on the relative expression of M RNA by means of Q-PCR. Use Alamut software to predict the splicing of SPINK1 exon mutation. Results 1, RT-PCR results show that SPINK1 exons mutation does not cause the abnormal transcriptional transcript to produce.2, Q-PCR results show SPINK1 mutation c.27del C (70.5 + 9.8). =0.0092), c.29GA (80 + 4.4, P=0.0029), c.98_99ins A (71.9 + 1.9, P=0.0015), c.190AG (82.2 + 4.1, P=0.0170), c.199CT (77.1 + 10.1, P=0.0070), c.203AG (87.4 + 7, P=0.0070). The m RNA expression of.27del C mutation increased (126.5 + 2.2, P=0.0023), and had no effect on c.98_99ins A (107.2 + 18.4, P=0.3606).4. Alamut software predicted that 7 mutations could affect the original splice site, c.190AG and other 10 mutations may produce new splice sites, and 12 mutations such as pretest c.199CT and 12 may reduce the activity of 8. There are 8 The mutation may enhance the ESEs activity.5. Compared with the results of the SPINK1 full-length gene model and the SPINK1 minigene model, the results of the RT-PCR results of the two models are similar, and all the SPINK1 abnormal transcripts caused by the c.194+2TC mutation can be displayed, and the other mutations of the exons have no effect on the SPINK1 transcript. But the Q-PCR results are different: minigene modulus The study showed that c.110AG (64.1 + 2, P=0.001), c.137TA (131.1 + 7.9, P=0.0211), c.194GA (44.5 + 6.4, P=0.0044) could affect the expression of M RNA, while the full length gene model did not suggest that the mutation changed the m RNA expression; c.190AG in the two models had the opposite results, and the full length gene model study showed that the mutation could reduce SPINK1 In the study of minigene model, the relative expression of M RNA was increased (121.4 + 2, P=0.0030). Conclusion 1. This study further identified the pathogenicity of the mutation in the exons of SPINK1, clarified the pathogenicity mechanism of the susceptibility mutation of the disease, and the common splicing analysis model minigene has some defects, suggesting the use of the whole system. The long gene model was studied and analyzed.

【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】：2017
【分類號(hào)】：R576

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