Neurobehavioral and molecular studies of gene-environment interactions in schizo

精神分裂症的发病机制可能涉及遗传易感性和 环境因素。在非遗传因素中，微生物感染与 精神疾病的发病率增加。我们认为，基于已识别的基因的实验模型 突变和可测量的环境因素可以极大地促进我们对 与精神分裂症相关的基因-环境相互作用机制。项目5的主要目标是 根据项目1-4确定的基因来表征新的GEI小鼠模型，InterAct 患有DISC1，并与精神分裂症有关。我们将评估神经行为的影响和 母体免疫激活和出生后早期慢性暴露小鼠GEI的分子生物学标志物 感染弓形虫。 我们预测，DISC1和/或其合作伙伴中的遗传操作将与相关的 产生神经行为和分子改变的环境因素与 精神分裂症和相关的精神障碍。 特定目标1将检验免疫激活和突变DISC1的产前相互作用将 协同作用导致成年后代出现精神分裂症样神经行为异常。特定目标2将 检验弓形虫慢性感染与出生后早期相互作用的假说 突变的DISC1将协同产生类似于阳性和 精神分裂症的认知症状。此外，我们将与项目6合作，评估 弓形虫感染DISCI突变小鼠神经行为病理学中的免疫复合体。 具体目标3将确定基因-环境相互作用的基因表达特征。 该项目将描述GEI相关的神经行为和分子后果 精神分裂症。这些结果将有助于确定可能调节相互作用的特定分子途径。 精神分裂症发病机制中基因突变和环境侮辱之间的关系。

The pathogenesis of schizophrenia is likely to involve multiple interactions between genetic vulnerability and environmental factors. Among non-genetic factors, microbial infections have been associated with the increased incidence of mental diseases. We believe that experimental models based on identified genetic mutations and measurable environment factors can significantly advance our understanding of the mechanisms of gene-environment interactions (GEI) relevant to schizophrenia. The main goal of Project 5 is to characterize new mouse models of GEI based on the genes that are identified by Projects 1-4, interact with DISC1, and have been associated with schizophrenia. We will evaluate the neurobehavioral effects and molecular biomarkers of GEI in mice exposed to either maternal immune activation or early postnatal chronic infection with Toxoplasma gondii. We predict that genetic manipulations in DISC1 and/or its partners will synergistically interact with relevant environmental factors to produce the neurobehavioral and molecular alterations consistent with aspects of schizophrenia and related mental disorders. Specific Aim 1 will test the hypothesis that prenatal interaction of immune activation and mutant DISC1 will synergistically lead to schizophrenia-like neurobehavioral abnormalities in adult offspring. Specific Aim 2 will test the hypothesis that early postnatal interactions between chronic infection with Toxoplasma gondii and mutant DISC1 will synergistically produce the neurobehavioral abnormalities resembling positive and cognitive symptoms of schizophrenia. In addtion, in collaboration with Project 6, we will evaluate a role of immunocomplexes in the neurobehavioral pathology in Toxoplasma-infected DISCI mutant mice. Specific Aim 3 will identify the gene expression signatures of gene-environment interactions. The project will characterize the neurobehavioral and molecular consequences of GEI relevant to schizophrenia. The results will help identify the specific molecular pathways that may mediate interplay between the genetic mutations and environmental insults in the pathogenesis of schizophrenia.