Pharmacogenomics Study Of Schizophrenia And Proteomics Study Of Fetus Nutrition Deficiency Rat Animal Model

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.