Schizophrenia: Molecular Markers of Disease Progression

描述(申请人提供)：精神分裂症是一种终生精神疾病，具有不同的表现和未知的病因。精神分裂症发病时的主要临床表现是精神病性症状；然而，随着疾病的进展，阴性症状变得更加突出。此外，许多其他神经学方面在病程中也会发生变化。影响精神分裂症发病后症状表现和病程的分子因素，以及治疗如何改变疾病的效果，仍然是重要的，基本上没有解决的问题。我们在这项应用中的目标是使用自动方法总基因表达分析(TOGA*/R)识别在疾病持续时间短或长的个体受试者的中枢神经系统中表达水平发生变化的基因。我们将从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产生基因表达谱：10名急性精神分裂症受试者(病程和5年)，10名慢性精神分裂症受试者(病程和22年)和20名对照，年龄和性别与两种疾病队列匹配(总共80份表达谱)。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，识别与疾病早期和晚期有关的基因对于了解疾病的发展将是重要的。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调查精神分裂症综合征的疾病异质性。我们将进一步表征抗精神病药物调节基因(以前在小鼠中发现)在人类精神分裂症受试者中的表达是如何改变的，以阐明抗精神病药物在人类中暴露的潜在后果。这将通过实时聚合酶链式反应、原位杂交和蛋白质印迹分析来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。总体而言，这些研究可能会带来有利于改变精神分裂症的病程、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.