Neocortical Transcriptome Changes in Schizophrenia

描述(申请人提供)：精神分裂症是一种复杂的疾病，其特征是新皮质上的多种功能和解剖变化。精神分裂症患者的前额叶皮质(PFC)功能障碍与工作记忆障碍有关，而颞叶上回(STG)的功能改变与精神病有关。此外，PFC和STG之间的功能分离可能是精神分裂症认知症状的原因之一。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以及它们之间的关系仍然大部分是未知的。不同性别的精神分裂症的表现与发病年龄、症状病理学、病前病史、神经影像表现、药物反应和大脑结构有关。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了潜在转录本的差异(或被其反映)。 这项应用围绕两个关键问题：1)在不同的大脑区域内和跨不同的大脑区域是否存在与精神分裂症相关的表达谱；以及2)与精神分裂症相关的表达变化是否因性别而异？在此背景下，我们建议使用3个特定目标来检验7个特定假设：目的1.比较12名男性精神分裂症受试者和匹配对照的前额叶(PFC)和颞叶上皮层(STG)的基因表达模式。目的2.比较12例女性精神分裂症患者和对照组前额叶(PFC)和颞叶上皮质(STG)的基因表达谱。AIMS 1和2将使用相同的方法，并比较转录本：A)使用全基因组HG_U133A和B Affymetrix微阵列。B)使用定制的、高灵敏度的聚合物基因芯片。这些涉及我们专利探针(专利申请正在进行中)的cDNA聚合物阵列将使我们能够改进和有针对性地评估许多转录本，这些转录本太稀疏，无法被目前可用的微阵列检测到。目的3.用原位杂交技术在转录水平上验证和定位微阵列未发现的基因表达变化到细胞类型A)，用免疫组织化学技术在蛋白质水平上验证和定位细胞类型A)。

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.