精神分裂症药物基因组学及孕期营养不良大鼠动物模型的蛋白质组学研究
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摘要
精神分裂症是一种严重的精神疾病，影响着全世界约1%的人口。精神分裂症是一组病因未明的精神疾病，临床表现为思维、情感和行为等多方面的障碍以及精神活动的不协调。该种疾病是由遗传因素和环境因素共同作用而发生，家系研究表明此疾病有较高的遗传性，但又不是简单的孟德尔型遗传。本论文主要围绕精神分裂症的基因组学、药物基因组研究以及可能导致成年精神分裂症的胎源性营养缺乏的大鼠蛋白质组研究。
HTR2C (5-HT2C)和精神分裂症利培酮治疗疗效的关联研究。该基因位于X染色体长臂2区4带(Xq24)，可翻译表达一种后突触G蛋白偶联受体。我们选取了HTR2C的5个SNP位点:rs3813929(-759C/T), rs518147(-697G/C), rs1023574, rs9698290, rs6318(Ser23Cys)在130名接受利培酮单一治疗的精神分裂症患者中进行关联分析，这些患者在接受利培酮治疗前都接受了为期8周的药物清洗期，以避免和其他药物的相互影响。通过研究我们发现位于HTR2C启动子区域的rs518147和邻近的rs1023574以及rs9698290位于同一个基因连锁区域(Gene block)，且都和中国女性精神疾病患者利培酮疗效改变有直接联系；进而通过显性模型(Dominant model)和隐性模型(Recessive model)对实验结果进行进一步分析发现，在rs518147和rs1023574位点上含有CC (G-)等位基因的女性患者在服用利培酮后，其疗效比CG或GG(G+)基因型的患者要好，而对于rs9698290的位点来说TT(C-)基因型会比CC或者CT(C+)效果要好。但是遗憾的是以上这些现象在男性患者中均没有发现，这可能是因为该基因位于性染色体，而造成的基因剂量(Dosage)影响不一样造成的。
早期生长反应基因(Early Growth Response,EGR)是一类重要的转录因子(Transcription factors)，其包含4个基因家族成员，分别为EGR1-4，用于调控神经元可塑性(Neuronal plasticity)基因的表达。在我们研究中首次在中国汉族人群中进行了关联研究来探讨EGR基因家族和精神分裂症之间可能的联系。我们一共选取了具有代表性的12个SNP在2044个样品(1022个正常对照样品，1022个精神分裂症样品)中进行了病例-对照实(Case-control)验。我们没有发现有任何SNP同精神分裂症或者其偏执亚型(Paranoid)和未分化亚型(Undifferentiated)有显著关联结果。最后我们用MDR (MultifactorDimensionality Reduction)来检测EGR基因家族之间的相互作用对精神分裂症致病性的研究，也没有任何阳性结果显示。这表明在我们的样品中，EGR基因不是主要致病性基因，但是我们需要更大样本量实验配合其他功能试验的验证。
研究室既往对三年饥荒时期出生的人成年后患精神分裂症流行病学研究表明，1959年出生的新生儿精神分裂症患病率是0.84%，而在饥荒期间出生的婴儿成年后患病率分别是2.15%，1.81%(男女患精神分裂症概率约相似)，分别是对照组的2倍。而这项研究在随后采用更大样本量，在广西柳州及周边18个村庄的研究中得到验证。于是我们构建了大鼠的饥荒研究模型来深入了解饥荒对成人胎源性疾病的分子机理研究。三组SD大鼠被随机的分成正常大鼠、中度缺乏孕期严重缺乏组别，待胎鼠成年后我们对其进行了行为学测试，分别包括旷场模型、强迫游泳模型、水迷宫和社交行为模型实验。然后对其海马及皮层脑区进行全蛋白质组学研究。
我们对正常和饥荒大鼠的海马和皮层的蛋白质组学采用同位素标记相对和绝对定量(i-TRAQ)平台寻找表达量发生显著变化的蛋白，然后利用IPA软件对这些差异蛋白进行通路分析。最后我们比较了海马和皮层中发生显著变化的通路，发现这些蛋白主要富集在以下三个通路中：糖代谢通路(CarbohydratePathway)、神经递质通路(Neuro-transmitter Pathway)和线粒体功能异常(MitochondrialDysfunction)。同时我们又使用了Western blot对一些显著发生变化的蛋白例如GNB1、GLUD1、GNAI1、STXBP1和HOMER1在正常组和严重营养缺乏组大鼠的海马和皮层中进行了验证试验。
本论文主要围绕精神分裂疾病展开，通过对疾病相关联的SNP位点进行研究,尝试用遗传学的方法找到可能的致病基因，及药物疗效预测基因靶点。同时探索胎源性营养不良对子代成年后行为变化并试图从蛋白组层面对这些现象进行解释，同时为精神分裂症的分子机理研究、抗精神病药物疗效评价预测提供了新的线索。
Schizophrenia is a common psychiatric disorder with a prevalence ofapproximately1%of the world population and is characterized bypsychotic symptoms such as hallucinations, delusions and thoughtdisturbances, etc. Former research indicated that schizophrenia is causedby both genetic risk and environmental factors, the linkage study showthe genetic factors work the major effects. Our studies are focusing on thgenetic and phamacogenetic study of schizophrenia, and proteomicsstudy of fetus nutrition deficiency rat animal model study. In total I havethree chapters:
Pharmacogenetic studyof HTR2Candrisperidone treatment inChinese schizophrenia patients.
Genetic associationstudy of EGRgene family with Chineseschizophrenia.
And proteomicsstudy offetus nutrition deficiency rat animalmodel.
The human HTR2C receptor gene is localized in sex chromosomeXq24. It is a post-synaptic G protein-linked receptor that activates boththe cyclic GMP and cerebrospinal fluid formation. We genotyped5singlenucleotide polymorphisms (SNPs) distributed the HTR2C and examinedthem for association with the Brief Psychiatric Rating Scale (BPRS)scores reduction changes in130Chinese schizophrenic patients followingan8-week period of risperidone monotherapy. All the patients receivedthe atypical antipsychotic drug treatment for their first time and have a4-week medication-free period before research. We found rs518147,rs1023574and rs9698290were significantly associated with risperidonetreatment in female patients (F=4.75, df=2, P=0.011; F=4.329, df=2andP=0.016; F=4.188, df=2, P=0.019). Our results indicate that variants inthe HTR2C promoter region are likely to affect the risperidonetherapeutic effect in female, however we did not find the same effect inChinese male patients. It may be helpful to investigate a combinationwith other clinical factors to predict atypical anti-psychotics efficacy inthe future study.
Early growth response (EGR) genes are thought to have a role in thepathogenesis of schizophrenia because of their conserved DNA bindingdomain and biological activity in neuronal plasticity. In this study we investigated the role of EGR1, EGR2, EGR3and EGR4within the EGRfamily. Taqman technology was used to examine12single nucleotidepolymorphisms (SNPs) covering these four genes in2044Chinese Hansubjects. Case-control analyses were performed to detect association ofthese4genes with schizophrenia and multifactor dimensionalityreduction (MDR) analysis was employed to examine their potential gene-gene interaction in schizophrenia. Neither allelic nor genotypic single-locus tests revealed any significant association between EGR1-4and therisk of schizophrenia nor was any such association found with regard tointeraction within EGR1-4(pmin=0.623, CV Consistency=10/10, otherdata not shown). We concluded that although multiple candidate genesare involved in schizophrenogenic development, the EGR family may notplay a major role in schizophrenia susceptibility in the Chinese Hanpopulation.
Our lab has done epidemiological study of schizophrenia during the1959-1961famine and found that the babies who was born during thoseyears have high risk of developing (OR=2) schizophrenia when theygrow up, and further larger sample validated this finding. Therefore thePhD thesis will build a fetus nutrition animal model to explore potentialmechanism of psychiatric disorder.
SD rats were divided into three groups randomly with normal/lowprotein and rare food limitation respectively, when their offspring grownup, we used open field, forced swimming model, water maze and socialinteraction model to test their behavior performance, when we finishedour animal model we attract rats’ hippocampusand cortexto test theirproteomics by using i-TRAQ platform. Through this advancedmethodology, we can get numbers of proteins which express differentlybetween normal and protein limited rat groups.
IPA analysis was used to analyze those differently expressed protein inhippocampus and cortex to test which pathway they belong to,respectively we compare those pathways together and found they sharesome common pathways as below: Carbohydrate Pathway, Neuro-transmitter Pathway and Mitochondrial Dysfunction. Some of the keyproteins (GNB1, GLUD1, GNAI1, STXBP1and HOMER1) werevalidated by western blotting method.
Our research did genetic study of schizophrenia, pharmacogeneticstudy of risperidone treatment in Chinese schizophrenia patients. Beyondthose genetic study, we also did animal model test to explore molecularmechanism of fetus protein restricted offspring which show differentbehavior when they grow up. Our research could help followers build a good understanding of psychiatric mechanism, provide hints forpredicting the treatment effect of different anti-psychiatric diseases,reduce the gap between basic lab work and clinical research and promotethe translational research in the future.
HTR2C (5-HT2C)和精神分裂症利培酮治疗疗效的关联研究。该基因位于X染色体长臂2区4带(Xq24)，可翻译表达一种后突触G蛋白偶联受体。我们选取了HTR2C的5个SNP位点:rs3813929(-759C/T), rs518147(-697G/C), rs1023574, rs9698290, rs6318(Ser23Cys)在130名接受利培酮单一治疗的精神分裂症患者中进行关联分析，这些患者在接受利培酮治疗前都接受了为期8周的药物清洗期，以避免和其他药物的相互影响。通过研究我们发现位于HTR2C启动子区域的rs518147和邻近的rs1023574以及rs9698290位于同一个基因连锁区域(Gene block)，且都和中国女性精神疾病患者利培酮疗效改变有直接联系；进而通过显性模型(Dominant model)和隐性模型(Recessive model)对实验结果进行进一步分析发现，在rs518147和rs1023574位点上含有CC (G-)等位基因的女性患者在服用利培酮后，其疗效比CG或GG(G+)基因型的患者要好，而对于rs9698290的位点来说TT(C-)基因型会比CC或者CT(C+)效果要好。但是遗憾的是以上这些现象在男性患者中均没有发现，这可能是因为该基因位于性染色体，而造成的基因剂量(Dosage)影响不一样造成的。
早期生长反应基因(Early Growth Response,EGR)是一类重要的转录因子(Transcription factors)，其包含4个基因家族成员，分别为EGR1-4，用于调控神经元可塑性(Neuronal plasticity)基因的表达。在我们研究中首次在中国汉族人群中进行了关联研究来探讨EGR基因家族和精神分裂症之间可能的联系。我们一共选取了具有代表性的12个SNP在2044个样品(1022个正常对照样品，1022个精神分裂症样品)中进行了病例-对照实(Case-control)验。我们没有发现有任何SNP同精神分裂症或者其偏执亚型(Paranoid)和未分化亚型(Undifferentiated)有显著关联结果。最后我们用MDR (MultifactorDimensionality Reduction)来检测EGR基因家族之间的相互作用对精神分裂症致病性的研究，也没有任何阳性结果显示。这表明在我们的样品中，EGR基因不是主要致病性基因，但是我们需要更大样本量实验配合其他功能试验的验证。
研究室既往对三年饥荒时期出生的人成年后患精神分裂症流行病学研究表明，1959年出生的新生儿精神分裂症患病率是0.84%，而在饥荒期间出生的婴儿成年后患病率分别是2.15%，1.81%(男女患精神分裂症概率约相似)，分别是对照组的2倍。而这项研究在随后采用更大样本量，在广西柳州及周边18个村庄的研究中得到验证。于是我们构建了大鼠的饥荒研究模型来深入了解饥荒对成人胎源性疾病的分子机理研究。三组SD大鼠被随机的分成正常大鼠、中度缺乏孕期严重缺乏组别，待胎鼠成年后我们对其进行了行为学测试，分别包括旷场模型、强迫游泳模型、水迷宫和社交行为模型实验。然后对其海马及皮层脑区进行全蛋白质组学研究。
我们对正常和饥荒大鼠的海马和皮层的蛋白质组学采用同位素标记相对和绝对定量(i-TRAQ)平台寻找表达量发生显著变化的蛋白，然后利用IPA软件对这些差异蛋白进行通路分析。最后我们比较了海马和皮层中发生显著变化的通路，发现这些蛋白主要富集在以下三个通路中：糖代谢通路(CarbohydratePathway)、神经递质通路(Neuro-transmitter Pathway)和线粒体功能异常(MitochondrialDysfunction)。同时我们又使用了Western blot对一些显著发生变化的蛋白例如GNB1、GLUD1、GNAI1、STXBP1和HOMER1在正常组和严重营养缺乏组大鼠的海马和皮层中进行了验证试验。
本论文主要围绕精神分裂疾病展开，通过对疾病相关联的SNP位点进行研究,尝试用遗传学的方法找到可能的致病基因，及药物疗效预测基因靶点。同时探索胎源性营养不良对子代成年后行为变化并试图从蛋白组层面对这些现象进行解释，同时为精神分裂症的分子机理研究、抗精神病药物疗效评价预测提供了新的线索。
Schizophrenia is a common psychiatric disorder with a prevalence ofapproximately1%of the world population and is characterized bypsychotic symptoms such as hallucinations, delusions and thoughtdisturbances, etc. Former research indicated that schizophrenia is causedby both genetic risk and environmental factors, the linkage study showthe genetic factors work the major effects. Our studies are focusing on thgenetic and phamacogenetic study of schizophrenia, and proteomicsstudy of fetus nutrition deficiency rat animal model study. In total I havethree chapters:
Pharmacogenetic studyof HTR2Candrisperidone treatment inChinese schizophrenia patients.
Genetic associationstudy of EGRgene family with Chineseschizophrenia.
And proteomicsstudy offetus nutrition deficiency rat animalmodel.
The human HTR2C receptor gene is localized in sex chromosomeXq24. It is a post-synaptic G protein-linked receptor that activates boththe cyclic GMP and cerebrospinal fluid formation. We genotyped5singlenucleotide polymorphisms (SNPs) distributed the HTR2C and examinedthem for association with the Brief Psychiatric Rating Scale (BPRS)scores reduction changes in130Chinese schizophrenic patients followingan8-week period of risperidone monotherapy. All the patients receivedthe atypical antipsychotic drug treatment for their first time and have a4-week medication-free period before research. We found rs518147,rs1023574and rs9698290were significantly associated with risperidonetreatment in female patients (F=4.75, df=2, P=0.011; F=4.329, df=2andP=0.016; F=4.188, df=2, P=0.019). Our results indicate that variants inthe HTR2C promoter region are likely to affect the risperidonetherapeutic effect in female, however we did not find the same effect inChinese male patients. It may be helpful to investigate a combinationwith other clinical factors to predict atypical anti-psychotics efficacy inthe future study.
Early growth response (EGR) genes are thought to have a role in thepathogenesis of schizophrenia because of their conserved DNA bindingdomain and biological activity in neuronal plasticity. In this study we investigated the role of EGR1, EGR2, EGR3and EGR4within the EGRfamily. Taqman technology was used to examine12single nucleotidepolymorphisms (SNPs) covering these four genes in2044Chinese Hansubjects. Case-control analyses were performed to detect association ofthese4genes with schizophrenia and multifactor dimensionalityreduction (MDR) analysis was employed to examine their potential gene-gene interaction in schizophrenia. Neither allelic nor genotypic single-locus tests revealed any significant association between EGR1-4and therisk of schizophrenia nor was any such association found with regard tointeraction within EGR1-4(pmin=0.623, CV Consistency=10/10, otherdata not shown). We concluded that although multiple candidate genesare involved in schizophrenogenic development, the EGR family may notplay a major role in schizophrenia susceptibility in the Chinese Hanpopulation.
Our lab has done epidemiological study of schizophrenia during the1959-1961famine and found that the babies who was born during thoseyears have high risk of developing (OR=2) schizophrenia when theygrow up, and further larger sample validated this finding. Therefore thePhD thesis will build a fetus nutrition animal model to explore potentialmechanism of psychiatric disorder.
SD rats were divided into three groups randomly with normal/lowprotein and rare food limitation respectively, when their offspring grownup, we used open field, forced swimming model, water maze and socialinteraction model to test their behavior performance, when we finishedour animal model we attract rats’ hippocampusand cortexto test theirproteomics by using i-TRAQ platform. Through this advancedmethodology, we can get numbers of proteins which express differentlybetween normal and protein limited rat groups.
IPA analysis was used to analyze those differently expressed protein inhippocampus and cortex to test which pathway they belong to,respectively we compare those pathways together and found they sharesome common pathways as below: Carbohydrate Pathway, Neuro-transmitter Pathway and Mitochondrial Dysfunction. Some of the keyproteins (GNB1, GLUD1, GNAI1, STXBP1and HOMER1) werevalidated by western blotting method.
Our research did genetic study of schizophrenia, pharmacogeneticstudy of risperidone treatment in Chinese schizophrenia patients. Beyondthose genetic study, we also did animal model test to explore molecularmechanism of fetus protein restricted offspring which show differentbehavior when they grow up. Our research could help followers build a good understanding of psychiatric mechanism, provide hints forpredicting the treatment effect of different anti-psychiatric diseases,reduce the gap between basic lab work and clinical research and promotethe translational research in the future.
引文
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