Neuroimmune Changes in Schizophrenia

精神分裂症的神经免疫变化

• 批准号: 7188736
• 负责人: Karoly Mirnics
• 金额: $ 36.88万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-12 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7188736
• 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; Class; Classification; Cognitive; Cohort Analysis; Complement; Complement component C1s; 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; Localized; MHC Class II Genes; Maternal Exposure; Measurement; Measures; Mediating; Metabolic; Methods; Microarray Analysis; Molecular; Molecular Profiling; Mus; Numbers; Pathway interactions; Patient currently pregnant; Pattern; Perinatal; Perinatal Hypoxia; Phosphotransferases; Predisposition; Prefrontal Cortex; Prevalence; Production; Psychotic Disorders; RNA; Range; Rattus; Reporting; Resolution; Risk; Sampling; Schizophrenia; Second Messenger Systems; Second Pregnancy Trimester; Short-Term Memory; Superior temporal gyrus; Synaptic Receptors; System; Temporal Lobe; Testing; Time; TimeLine; Tissues; Transcript; Validation; Virus Diseases; base; behavior test; cell type; chemokine; cohort; cytokine; day; density; design; exposed human population; fetal; frontal lobe; human prostaglandin D2 receptor; human subject; human tissue; interest; maternal serum; mature animal; mind control; mouse model; prenatal; prenatal exposure; prepulse inhibition; ranpirnase; research study; response; size

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）：第二个三个月的孕产妇感染和围产期缺氧是免疫系统和促炎性细胞因子的有效活化剂，这可能会影响正常的脑发育，从而倾向于发展精神分裂症。在我们最近的精神分裂症患者前额叶皮层的大脑表达分析实验中，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，炎性细胞因子诱导的转录组特征，包括可诱导的干扰素诱导（IFITM家族），MHC II类（DP，DR和DQ类），热休克蛋白（HSP28和HSP70），补体系统（C1和C3）以及其他转录。此外，迄今为止，精神分裂症的所有高密度微阵列研究都报告了与免疫系统有关的表达变化。动物研究还支持精神分裂症中看到的生物学变化与细胞因子表达之间的紧密联系。特别是，用单剂量的合成细胞因子诱导剂多核苷类 - 吡啶蛋白丁基替甲酸[Poly（L：C）]对大鼠或小鼠进行产前治疗会导致潜在的潜在抑制作用，前抑制前抑制（PPI）过度抑制（PPI），多发性抑制作用，双刺激性和精神病。这表明病毒感染不是必需的。孕产妇免疫反应似乎是引起胎儿脑发育变化的关键。根据这些发现，我们假设通过促炎性细胞因子诱导，各种环境影响会触发发展中大脑的强烈转录组反应，这可能会持续到成人生活中。为了检验这一假设，我们将针对小鼠和人类设计全面的免疫自定义DMA微阵列（AIM 1），并分析前额叶皮层（PFC），上颞回（STG）和小脑（Cerebellum（CBL）和小脑（CBL）的免疫转录组）在30名受试者中与精神分裂症和匹配的控制（AIM 2）。此外，我们将评估在用poly（l：c）在不同时间点处理的小鼠的相应大脑区域的转录组变化（AIM 3）。在鉴定人类和小鼠数据集的常见基因表达变化后（AIM 4），我们将通过qPCR验证并通过原位杂交定位于细胞类型，最有希望的基因表达变化（AIM 5）。我们预测，具有精神分裂症的受试者将显示特定免疫反应基因的表达持续改变，这些特定免疫反应基因直接受到促炎性细胞因子的调节，并且在青少年/成年小鼠的大脑中也会观察到其中一些表达变化，这些变化暴露于聚（L：C）介导的胚胎生命期间的多（L：C）介导的细胞因子诱导。这些通常观察到的人类组织和小鼠模型之间的免疫转录本变化将有助于我们定义可测试的分子底物，环境影响易感精神分裂症。