Neocortical Transcriptome Changes in Schizophrenia

描述（由申请人提供）：精神分裂症是一种复杂的疾病，以新皮层的多种功能和解剖变化为特征。精神分裂症患者前额叶皮质（PFC）功能障碍与工作记忆缺陷有关，而颞上回（STG）功能变化与精神病有关。此外，PFC和STG之间的功能断开可能导致精神分裂症的认知症状。尽管已经报道了STG和PFC中单个基因表达的变化，但这些区域之间的转录组差异以及它们之间的关系仍然未知。不同性别的精神分裂症的表现与发病年龄、症状、病前病史、神经影像学发现、药物反应性和大脑结构的差异有关。功能和结构研究表明，精神分裂症患者的STG和PFC存在性别差异。然而，我们不知道这些性别差异是否反映（或被反映）底层转录组的差异。

DESCRIPTION (provided by applicant): Schizophrenia is a complex disorder that is characterized by multiple functional and anatomical changes across the neocortex. Dysfunction of the prefrontal cortex (PFC) in schizophrenia has been associated with deficits of working memory, while functional changes in the superior temporal gyrus (STG) have been related to psychosis. In addition, a functional disconnection between the PFC and STG may contribute to the cognitive symptoms of schizophrenia. Although changes in the expression of individual genes have been reported in both STG and PFC, the transcriptome differences across these regions and the relationship between them remain mostly unknown. The presentation of schizophrenia across genders has been associated with differences in age of onset, symptomathology, premorbid history, neuroimaging findings, drug responsiveness and brain structure. Functional and structural studies suggest that gender differences are present in the STG and PFC of subjects with schizophrenia. However, we do not know if these gender differences reflect (or are reflected by) differences in the underlying transcriptomes. This application is focused around two critical questions: 1) Is there a schizophrenia-related expression profile within and across different brain regions and 2) Are schizophrenia-related expression changes different across genders? In this context, we propose to test seven specific hypotheses using 3 specific aims: Aim 1. Compare gene expression pattern in 12 MALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices. Aim 2. Compare gene expression pattern in 12 FEMALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices. Aims 1 and 2 will share the same methodology, and compare the transcriptomes: A) Using whole genome HG_U133A and B Affymetrix microarrays. B) Using custom-made, high-sensitivity polymer cDNA microarrays. These cDNA polymer arrays, involving our proprietary probes (patent application in progress) will allow us an improved and targeted assessment of many transcripts that are too sparse to be detected by the currently available microarrays. Aim 3. Verify and localize the microarray-uncovered gene expression changes to cell types A) at transcript level using in situ hybridization and B) at protein level using immunohistochemistry.