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，其特征在于跨新皮层的多种功能和解剖学变化。精神分裂症患者的前额叶皮质（PFC）功能障碍与工作记忆缺陷有关，而上级颞回（STG）的功能改变与精神病有关。此外，PFC和STG之间的功能断开可能有助于精神分裂症的认知症状。虽然在STG和PFC中已经报道了单个基因表达的变化，但这些区域的转录组差异及其之间的关系仍然是未知的。精神分裂症的性别表现与发病年龄、病理学、病前病史、神经影像学表现、药物反应性和脑结构的差异有关。功能和结构的研究表明，性别差异存在于精神分裂症患者的STG和PFC。然而，我们不知道这些性别差异是否反映了（或反映了）潜在转录组的差异。 该应用程序集中在两个关键问题：1）在不同的大脑区域内和跨不同的大脑区域是否存在精神分裂症相关的表达谱，以及2）精神分裂症相关的表达变化在性别之间是否不同？在这种情况下，我们建议使用3个具体目标来测试7个具体假设：目标1。比较12名男性精神分裂症患者和对照组前额叶（PFC）和上级颞叶（STG）皮质的基因表达模式。目标2.比较12名女性精神分裂症患者和对照组前额叶（PFC）和上级颞叶（STG）皮质的基因表达模式。目的1和2将共享相同的方法，并比较转录组：A）使用全基因组HG_U133 A和B Affymbox微阵列。B）使用定制的高灵敏度聚合物cDNA微阵列。 这些cDNA聚合物阵列，涉及我们的专有探针（专利申请正在进行中），将使我们能够改进和有针对性的评估许多转录太稀疏，目前可用的微阵列检测。目标3.使用原位杂交在转录物水平和使用免疫组织化学在蛋白质水平验证和定位细胞类型A）和B）的微阵列未覆盖的基因表达变化。

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.