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Neuroimmune Changes in Schizophrenia

精神分裂症的神经免疫变化

基本信息

批准号：
8034743
负责人：
Karoly Mirnics
金额：
$ 34.09万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-12 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8034743
关键词：
Acids Adolescent Adult Affect Affective Age Animals Antipsychotic Agents Area Atrophic Autopsy Behavior assessment Behavioral Biological Biological Assay Brain Brain Pathology Brain region Cell Adhesion Molecules Cerebellar vermis structure Cerebellum Cognitive Cohort Analysis Complex Custom DNA Data Data Set Development Disease Dose Embryo Ensure Environmental Risk Factor Etiology Event Experimental Designs Exposure to Family Figs - dietary Functional disorder Gene Expression Gene Expression Alteration Gene Expression Profile Gene Proteins Genes Harvest Heat shock proteins Heat-Shock Proteins 70 Homologous Gene Human Immune Immune Response Genes Immune response Immune system Immunohistochemistry In Situ Hybridization Individual Infection Inflammatory Interferons Life Link MHC Class II Genes Maternal Exposure Measurement Measures Mediating Metabolic Methods Microarray Analysis Molecular Molecular Profiling Mus Pathway interactions Pattern Perinatal Perinatal Hypoxia Phosphotransferases Predisposition Prefrontal Cortex Prevalence Production Psychotic Disorders RNA Rattus Reporting Resolution Risk Sampling Schizophrenia Second Messenger Systems Second Pregnancy Trimester Short-Term Memory Superior temporal gyrus Synaptic Receptors Temporal Lobe Testing Time TimeLine Tissue Model Tissues Transcript Validation Virus Diseases base behavior test candidate selection cell type chemokine cohort complement system cytokine density design exposed human population fetal frontal lobe human subject human tissue interest maternal serum mature animal mind control mouse model offspring pregnant prenatal prenatal exposure prepulse inhibition ranpirnase research study response young adult

项目摘要

DESCRIPTION (provided by applicant): Second trimester maternal infection and perinatal hypoxia are potent activators of the immune system and pro-inflammatory cytokines, which may affect normal brain development, thus predisposing for developing schizophrenia. In our recent brain expression profiling experiments of the prefrontal cortex of subjects with schizophrenia, we have uncovered a number of robust gene expression changes related to the immune response. These changes, verified by qPCR, suggest an inflammatory cytokine-induced transcriptome signature that include interferon-inducible (IFITM family), MHC class II (DP, DR and DQ classes), heat-shock proteins (HSP28 and HSP70), complement system (C1 and C3) and other transcripts. In addition, virtually all high-density microarray studies of schizophrenia to date have reported expression changes related to the immune system. Animal studies also support a strong link between biological changes seen in schizophrenia and cytokine expression. In particular, prenatal treatment of rats or mice with a single dose of the synthetic cytokine inducer polyriboinosinic-polyribocytidilic acid [poly(l:C)] leads to postpubertal emergence of disrupted latent inhibition, prepulse inhibition (PPI), dopaminergic hyperfunction and brain pathology in the offspring. This suggests that viral infection is not necessary; the maternal immune response appears to be key in causing changes in fetal brain development. Based on these findings we hypothesize that various environmental influences, via pro-inflammatory cytokine induction, trigger a strong transcriptome response in the developing brain that may persist into adult life. To test this hypothesis, we will design comprehensive immune custom DMA microarrays for mouse and human (Aim 1) and analyze the immune transcriptome of prefrontal cortex (PFC), superior temporal gyrus (STG) and cerebellum (CBL) in 30 subjects with schizophrenia and matched controls (Aim 2). Furthermore, we will assess transcriptome changes in the corresponding brain regions of mice treated at various time points with poly(l:C) (Aim 3). After identification of the common gene expression changes across the human and mouse datasets (Aim 4) we will verify by qPCR and localize to cell type by in situ hybridization the most promising gene expression changes (Aim 5). We predict that subjects with schizophrenia will show consistently altered expression of specific immune response genes that are directly regulated by pro-inflammatory cytokines, and that some of these expression changes will also be observed in the brain of adolescent/adult mice that were exposed to poly(l:C)-mediated cytokine induction during embryonic life. These commonly observed immune transcript changes between the human tissue and mouse model(s) will help us define a testable molecular substrate by which environmental influences predispose for developing schizophrenia.

描述（由申请人提供）：妊娠中期母体感染和围产期缺氧是免疫系统和促炎细胞因子的强效激活剂，可能影响正常的大脑发育，从而诱发精神分裂症。在我们最近对精神分裂症受试者的前额叶皮层进行的大脑表达谱实验中，我们发现了许多与免疫反应相关的强大基因表达变化。通过qPCR验证的这些变化表明炎性丝氨酸诱导的转录组特征，其包括干扰素诱导型（IFITM家族）、MHC II类（DP、DR和DQ类）、热休克蛋白（HSP 28和HSP 70）、补体系统（C1和C3）和其他转录物。此外，迄今为止，几乎所有精神分裂症的高密度微阵列研究都报告了与免疫系统相关的表达变化。动物研究也支持在精神分裂症中观察到的生物学变化与细胞因子表达之间的强烈联系。特别是，用单剂量的合成细胞因子诱导剂聚核糖肌苷酸-聚核糖胞苷酸[poly（I：C）]对大鼠或小鼠进行产前治疗，导致后代在青春期后出现中断的潜伏抑制、前脉冲抑制（PPI）、多巴胺能功能亢进和脑病理学。这表明病毒感染不是必要的;母体免疫反应似乎是导致胎儿大脑发育变化的关键。基于这些发现，我们假设各种环境影响，通过促炎细胞因子诱导，在发育中的大脑中引发强烈的转录组反应，可能持续到成年。为了验证这一假设，我们将为小鼠和人类设计全面的免疫定制DMA微阵列（目标1），并分析30名精神分裂症患者和匹配对照组的前额叶皮层（PFC），上级颞回（STG）和小脑（CBL）的免疫转录组（目标2）。此外，我们将评估在不同时间点用poly（I：C）处理的小鼠的相应脑区域中的转录组变化（目的3）。在人类和小鼠数据集中鉴定出共同的基因表达变化后（目标4），我们将通过qPCR进行验证，并通过原位杂交将最有希望的基因表达变化定位于细胞类型（目标5）。我们预测，精神分裂症受试者将表现出一致的特定免疫应答基因的表达改变，这些基因直接受促炎细胞因子的调节，并且在胚胎期暴露于poly（I：C）介导的细胞因子诱导的青少年/成年小鼠的大脑中也将观察到这些表达变化中的一些。这些在人类组织和小鼠模型之间经常观察到的免疫转录物变化将帮助我们定义一个可测试的分子底物，环境影响通过该底物易患精神分裂症。