Project 4: Refining transcriptional networks in MIA

项目 4：完善 MIA 中的转录网络

• 批准号: 10214322
• 负责人: DANIEL H GESCHWIND
• 金额: $ 38.93万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10214322
• 关键词: Address; Affect; Animal Model; Archives; Behavior; Behavioral; Biological; Biological Markers; Blood; Brain; Brain region; Cells; Collaborations; Corpus striatum structure; Data; Development; Disease susceptibility; Dose; Environmental Risk Factor; FOXP3 gene; Female; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Human; Image; Immune; Immune response; Immunologic Factors; Individual; Interneurons; Intervention; Link; Male Adolescents; Measures; Mediating; Mental disorders; Methylation; Modeling; Molecular; Mothers; Multivariate Analysis; Mus; Neurobiology; Neurodevelopmental Disorder; Neuroimmune; Neuroimmunomodulation; Neurons; Nuclear; Outcome; Pathway Analysis; Pathway interactions; Phenotype; Placentation; Poly I-C; Population; Predisposition; Prefrontal Cortex; Pregnancy; Regulator Genes; Regulatory T-Lymphocyte; Risk; Risk Factors; Sampling; Schizophrenia; Sex Differences; Spliced Genes; Structure; Synapses; System; Time; Tissues; Work; autism spectrum disorder; base; behavioral outcome; brain behavior; brain cell; cell type; cohort; cytokine; data integration; design; fetal; genetic epidemiology; human disease; immune activation; immunoreactivity; insight; male; mouse model; neurobehavioral; neuropathology; neuropsychiatric disorder; nonhuman primate; novel; offspring; postnatal; prepuberty; prevent; regional difference; repetitive behavior; resilience; response; sex; success; transcriptome; transcriptome sequencing; transcriptomics; whole genome

PROJECT SUMMARY – PROJECT 4 Despite substantial advances in genetics, there is a lack of understanding of how environmental or fetal- maternal factors influence neuropsychiatric disease susceptibility. Over the last 4 years we have shown that maternal immune activation (MIA), a risk factor for neurodevelopmental disorders, results in long lasting regional changes in gene expression in the brain of mice and non-human primates (NHP). One set of key observations has been that variability in the maternal immune response, driven by baseline differences in immunoreactivity (BIR), likely contributes to the variability in offspring outcomes. These observations provide us with the opportunity to mechanistically connect maternal immune factors with subsequent resilience or sus- ceptibility in changes in brain and behavior in offspring. By transcriptomic profiling of immune cells from the mothers before and during pregnancy following MIA, as well as brain cells from MIA and control offspring, at the bulk tissue and single cell level, this project provides a molecular and cellular framework for understanding the basis for differential outcomes in offspring caused by MIA across species. Specifically, we will distinguish how differential cortico-striatal gene expression relates to BIR before pregnancy and to changes in maternal immune responses during MIA. First, in collaboration with Project 3 we will characterize changes in gene expression in specific cell types in dorsolateral prefrontal cortex (PFC) and striatum in NHP MIA off- spring using bulk RNAseq and nucSeq to measure transcriptome changes in cortical neurons, striatal neurons, and glial populations, including males and females (controls and MIA) from mothers with a compre- hensive assessment of their immune response and fetal-placental development. Second, our team will characterize and integrate the transcriptional signature caused by MIA to identify changes in gene ex- pression in specific cell types in the PFC and striatum of susceptible and resilient mouse MIA offspring characterized in Project 2. Third, these data will be combined with transcriptomic markers in blood from susceptible and resilient female mice and NHPs before and during pregnancy from Project 1, to identify changes in gene expression in specific immune cell types associated with MIA and variability in BIR. Fourth, we will integrate molecular data with outcomes and maternal premorbid immune response to identify biomarkers and mechanistic models of susceptibility and resilience in mothers and offspring We will identify changes associated with maternal parameters including in blood immune cells (Aim 3), cytokine pro- files (Project 1) and maternal sickness (Projects 2 and 3), and associate them with offspring response (brain cytokines, behavior: Projects 1, 2, 3; imaging changes in humans: Project 5). These data will be used to inform mechanistic models that link neuroimmune responses to molecular pathways and specific cellular responses, to the emergence of altered brain structure and behavior. The single platform, cross-species design will enable us to more definitively determine the relationship of these changes to neuropsychiatric disease in humans.

项目概要-项目4 尽管在遗传学方面取得了重大进展，但人们对环境或胎儿- 母亲因素影响神经精神疾病的易感性。在过去的四年里，我们已经证明， 母体免疫激活（MIA）是神经发育障碍的一个危险因素， 小鼠和非人灵长类动物（NHP）脑中基因表达的区域变化。一套钥匙 观察结果表明，母体免疫反应的变异性，由基线差异驱动， 免疫反应性（BIR），可能有助于后代结果的变异性。这些观察提供 我们有机会机械地将母体免疫因素与随后的恢复力或持续性联系起来， 对后代大脑和行为变化的敏感性。通过免疫细胞的转录组学分析， MIA后怀孕前和怀孕期间的母亲，以及MIA和对照后代的脑细胞，在 该项目提供了一个分子和细胞框架， MIA引起的不同物种后代结果的基础。具体来说，我们将区分 皮质-纹状体基因表达差异如何与孕前BIR和母体 MIA期间的免疫反应。首先，与项目3合作，我们将描述基因的变化， NHP MIA关闭时背外侧前额叶皮质（PFC）和纹状体中特定细胞类型的表达， Spring使用批量RNAseq和nucSeq测量皮质神经元、纹状体神经元和海马神经元中的转录组变化。 神经元和神经胶质细胞群，包括来自患有compre的母亲的雄性和雌性（对照和MIA）， 全面评估其免疫反应和胎儿-胎盘发育。第二，我们的团队将 表征和整合MIA引起的转录特征，以识别基因表达的变化， 易感和恢复性小鼠MIA后代PFC和纹状体中特定细胞类型的表达 项目2的特点。第三，这些数据将与血液中的转录组标记物相结合， 项目1中的易感和恢复力强的雌性小鼠和NHP在妊娠前和妊娠期间， 与MIA相关的特定免疫细胞类型的基因表达变化和BIR的变异性。第四、 我们将整合分子数据与结果和母体病前免疫反应， 母亲和后代的易感性和恢复力的生物标志物和机制模型 确定与母体参数相关的变化，包括血液免疫细胞（Aim 3）、细胞因子前体 文件（项目1）和孕产妇疾病（项目2和3），并将它们与后代的反应（大脑 细胞因子，行为：项目1，2，3;人类成像变化：项目5）。这些数据将用于通知 将神经免疫反应与分子途径和特定细胞反应联系起来的机制模型， 大脑结构和行为的改变单一平台，跨物种设计将使 我们更明确地确定这些变化与人类神经精神疾病的关系。