【摘要】：第一部分精神分裂癥關(guān)聯(lián)分析 精神分裂癥易感基因和易感位點的研究已經(jīng)取得了很多成果,位于mRNA3'-UTR的單核苷酸多態(tài)性(SNP)可能會影響miRNA與mRNA的結(jié)合并最終導(dǎo)致疾病的發(fā)生。大量研究表明,miRNA在精神分裂癥發(fā)病過程中發(fā)揮重要作用,但是mRNA3'-UTR的SNPs是否通過改變miRNA和3'-UTR的結(jié)合,進(jìn)而影響基因的表達(dá),從而在精神分裂癥發(fā)病過程中起作用依然不清楚。因此,十分有必要探究這些SNPs與精神分裂癥的關(guān)聯(lián)。 我們采用生物信息學(xué)的辦法篩選了位于425個精神分裂癥候選基因的3'-UTR區(qū)域的803個SNPs�；趍iRBase數(shù)據(jù)庫,通過用miRanda, microinspector, PicTar和RNAhybrid等計算這些miRNA與SNPs結(jié)合的自由能,選擇9個最有可能影響miRNA與3'-UTR區(qū)域結(jié)合的SNPs在漢族人群中驗證,結(jié)果發(fā)現(xiàn),rs3219151(C＞T, GABRA6)可以顯著降低精神分裂癥發(fā)病風(fēng)險(OR=0.8121, P=0.008, P adjust=0.03)。 本研究說明,采用新的候選SNPs的選擇方法有利于加深對精神分裂癥的認(rèn)識,同時可以提高候選SNPs的篩選效率,為進(jìn)一步研究miRNA在精神分裂癥發(fā)病過程中的作用提供研究基礎(chǔ)。 第二部分母親孕期饑荒致子代精神分裂癥高度易感機(jī)制研究 流行病學(xué)研究已經(jīng)證明出生前饑荒暴露可導(dǎo)致精神分裂癥風(fēng)險上升,出生在饑荒年代的人精神分裂癥的相對易感性是正常人的近兩倍,國內(nèi)外學(xué)者對出生前饑荒暴露導(dǎo)致精神分裂癥發(fā)病風(fēng)險上升的機(jī)制研究一直沒有中斷過。已有研究表明,母親孕期營養(yǎng)不良可以導(dǎo)致成年子代大腦的結(jié)構(gòu)和功能精神分裂癥樣異常,但是饑荒導(dǎo)致成年子代精神分裂癥易感性增加的機(jī)制至今不明。 為了研究饑荒導(dǎo)致子代精神分裂癥發(fā)病風(fēng)險上升的機(jī)制,我們建立了大鼠饑荒動物模型RLP50,對子代大鼠海馬和前額葉皮質(zhì)全基因組基因表達(dá)情況進(jìn)行分析,發(fā)現(xiàn)RP50組后代前額葉皮質(zhì)中神經(jīng)遞質(zhì)相關(guān)受體表達(dá)紊亂,并且嗅覺相關(guān)基因表達(dá)也有差異。通過對海馬的研究發(fā)現(xiàn)大規(guī)�；虮磉_(dá)重編程,其中表達(dá)差異明顯的基因主要集中在突觸功能相關(guān)和轉(zhuǎn)錄調(diào)控功能相關(guān)的功能區(qū)域；緊接著我們對海馬全基因組甲基化情況進(jìn)行全基因組甲基化分析,結(jié)果表明饑荒組RLP50后代出現(xiàn)一個系統(tǒng)的甲基化重編程,主要表現(xiàn)是基因的高甲基化(86.9%)。對發(fā)生甲基化差異的基因進(jìn)行GO分析發(fā)現(xiàn)：差異甲基化基因和差異表達(dá)基因共同集中在相同的功能區(qū)域,分別是：質(zhì)膜,RNA聚合酶Ⅱ活性調(diào)控,細(xì)胞環(huán)路,金屬陽離子運輸,鈣離子通道活性和神經(jīng)元投射環(huán)路等。其中最顯著的是質(zhì)膜(表達(dá)譜中P=2.37×10-9,DNA甲基化組中P=5.36×10-9)。于此同時我們發(fā)現(xiàn),Mecp2和slc2a1兩個基因在海馬中表達(dá)下調(diào),并且在海馬中DNA甲基化顯著增高。 綜上,本研究表明母親孕期饑荒導(dǎo)致成年子代海馬和前額葉皮質(zhì)中基因表達(dá)重編程,致使大量基因轉(zhuǎn)錄活性下降,這種機(jī)制可能會導(dǎo)致精神分裂癥的發(fā)生。
[Abstract]:The first part of the study of schizophrenia association analysis of schizophrenia susceptibility genes and susceptibility sites has achieved a lot of results. Single nucleotide polymorphisms (SNP) located in mRNA3'-UTR may affect the binding of miRNA to mRNA and eventually lead to disease. A large number of studies have shown that miRNAs play an important role in the pathogenesis of schizophrenia, but it is still unclear whether the SNPs of mRNA3'-UTR affects gene expression by altering the binding of miRNA and 3'-UTR, and thus plays an important role in the pathogenesis of schizophrenia. Therefore, it is necessary to explore the association between these SNPs and schizophrenia. We used bioinformatics to screen 803 SNPs in the 3'-UTR region of 425 schizophrenic candidate genes. Based on miRBase database, by using miRanda, microinspector, PicTar and RNAhybrid to calculate the free energy of the combination of miRNA and SNPs, we selected 9 SNPs which are most likely to affect the combination of miRNA and 3'-UTR in Han population. The results showed that rs3219151 (C > T, GABRA6) could significantly reduce the risk of schizophrenia (ORO 0.8121, P < 0.008, P adjust=0.03). This study shows that the new method of selecting candidate SNPs can help to deepen the understanding of schizophrenia, improve the screening efficiency of candidate SNPs, and provide a basis for further study on the role of miRNA in the pathogenesis of schizophrenia. The second part of the study on the mechanism of high susceptibility to maternal famine-induced schizophrenia during pregnancy Epidemiology studies have shown that exposure to pre-natal famine can lead to an increase in the risk of schizophrenia. The relative susceptibility of people born in famine years to schizophrenia is nearly twice as high as that of normal people. Scholars at home and abroad have not interrupted the research on the mechanism of the rise of risk of schizophrenia caused by pre-birth famine exposure. Studies have shown that maternal malnutrition during pregnancy can lead to structural and functional schizophrenia like abnormalities in the brain of adult offspring, but the mechanism of increased susceptibility to schizophrenia caused by famine is still unknown. In order to study the mechanism of increasing the risk of schizophrenia in offspring induced by famine, we established an animal model of famine, RLP50, to analyze the gene expression of the whole genome in hippocampus and prefrontal cortex of rats. It was found that the expression of neurotransmitter-related receptors and olfactory related genes in prefrontal cortex of RP50 group were different. Through the study of hippocampus, it was found that large-scale gene expression reprogramming, in which the difference in gene expression mainly concentrated in synaptic function related and transcriptional regulatory function related functional areas; Then we analyzed the whole genome methylation of hippocampus. The results showed that there was a systematic methylation reprogramming in the progeny of RLP50 in famine group, which was mainly characterized by gene hypermethylation (86.9%). Go analysis showed that the differential methylation genes and differentially expressed genes were concentrated in the same functional region. They were: plasma membrane RNA polymerase 鈪，

本文編號：2193659