Schizophrenia: Molecular Markers of Disease Progression

描述（由申请人提供）：精神分裂症是一种表现多样、病因不明的终生精神疾病。精神分裂症发病时的主要临床表现是精神症状；然而，随着病情的进展，阴性症状变得更加突出。此外，许多其他神经系统方面在疾病过程中也会发生变化。影响精神分裂症症状表现和发病后病程的分子因素以及治疗如何改变疾病的影响仍然是重要且本质上尚未解决的问题。我们在此应用中的目标是使用自动化方法总基因表达分析 (TOGA*/R) 来识别那些患有短期或长期疾病的个体受试者中枢神经系统中表达水平发生改变的基因。我们将从处于不同疾病阶段的个体精神分裂症受试者的前额叶和颞叶皮质生成基因表达谱：10 名急性精神分裂症受试者（疾病持续时间 <5 年）、10 名慢性精神分裂症受试者（疾病持续时间 >22 年）和 20 名对照，年龄和性别与两个疾病队列匹配（总共 n = 80 个表达谱）。由于疾病早期的正确治疗被认为对疾病的结果有有益的影响，因此识别疾病早期和晚期阶段涉及的基因对于了解疾病进展非常重要。我们还将通过区分所有精神分裂症个体亚群中存在的基因表达模式来研究精神分裂症综合征的疾病异质性。我们将进一步描述抗精神病药物调节基因（之前在小鼠中鉴定出）的表达在精神分裂症人类受试者中如何改变，以阐明人类暴露于抗精神病药物的潜在后果。 这将通过实时 PCR、原位杂交和蛋白质印迹分析测量慢性精神分裂症受试者死后大脑样本中候选基因的表达差异来实现。总体而言，这些研究可能会带来有利于改变精神分裂症病程、治疗和结果的方法。

DESCRIPTION (provided by applicant): Schizophrenia is a life-long mental illness with variable expression and unknown etiology. The major clinical manifestations of schizophrenia at disease onset are psychotic symptoms; however, as the illness progresses the negative symptoms become more predominant. In addition, many other neurological aspects change over the course of illness. The molecular factors that influence symptom presentation and the course of schizophrenia after its onset and how treatment modifies the effects of illness remain important and essentially unaddressed questions. Our goals in this application are to identify genes that have altered levels of expression in the CNS of individual subjects who have had a short or long duration of illness using the automate method Total Gene expression Analysis (TOGA*/R). We will generate gene expression profiles from the prefrontal and temporal cortices of individual schizophrenic subjects at different stages of illness: 10 acute schizophrenic subjects (illness duration <5 yrs), 10 chronic schizophrenic subjects (illness duration >22 yrs) and 20 controls, age- and sex- matched to both disease cohorts (n=80 expression profiles total). Since correct treatment early in the illness is thought to have a beneficial affect on the outcome of the disease, the identification of genes involved in the early versus late stages of disease will be important for understanding disease progression. We will also investigate disease heterogeneity in the schizophrenia syndrome by distinguishing gene expression patterns that are present in subsets of all schizophrenic individuals. We will further characterize how the expression of antipsychotic drug-regulated genes (previously identified in mice) is altered in human subjects with schizophrenia in order to elucidate potential consequences of antipsychotic drug exposure in humans. This will be accomplished by measuring expression differences of candidate genes in postmortem brain samples from chronic schizophrenic subjects by real-time PCR, in situ hybridization and Western blot analyses. Overall, these studies may lead to approaches that will favorably alter the course, treatment and outcome of schizophrenia.