Role of glia and inflammation in altered synapse development in schizophrenia

神经胶质细胞和炎症在精神分裂症突触发育改变中的作用

• 批准号: 8836668
• 负责人: Shinichi Kano
• 金额: $ 24.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-22 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836668
• 关键词: Address; Adolescence; Adult; Affect; Astrocytes; Atherosclerosis; Autoimmune Diseases; Biochemical; Brain; CD3 Antigens; Cells; Complement; Complement 1q; Data; Defect; Development; Diabetes Mellitus; Disease; Drug Metabolic Detoxication; Early Intervention; Enzyme-Linked Immunosorbent Assay; Functional disorder; Gene Expression; Genes; Genetic Predisposition to Disease; Glutamates; Glutathione S-Transferase; Goals; Immune; Immunohistochemistry; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Lead; Life; Mediating; Mediator of activation protein; Microglia; Modeling; Mus; Mutant Strains Mice; MyD88 protein; Myelogenous; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Oxidative Stress; Oxygen; Pathology; Patients; Play; Predisposition; Production; RNA Interference; Reporting; Research; Research Personnel; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Role; Schizophrenia; Signal Transduction; Staging; Stress; Subfamily lentivirinae; Synapses; System; Testing; Time; Training; Virus; abstracting; astrogliosis; cytokine; frontal lobe; glial cell development; hippocampal pyramidal neuron; in vivo; knock-down; neuropsychiatry; new therapeutic target; postnatal

Project Summary/Abstract Disturbance in brain development during adolescence may underlie schizophrenia (SZ). Although many reports showed that astrogliosis is not observed in SZ, accumulating evidence suggests that altered function of astrocytes and microglia as well as aberrant immune/inflammatory responses may also underlie SZ. Nonetheless, it is unclear whether or to what extent glial cells and inflammation are involved in altered brain development during adolescence. Recently, we have found that the expression of immune/stress related genes is altered in live neuronal cells derived from SZ patients. The most affected genes include glutathione S-transferase theta 2 (GSTT2) gene, which regulates cellular detoxification system and protects cells from reactive oxygen metabolites. Oxidative stress activates innate immune signaling and contributes to inflammation in various diseases such as diabetes, atherosclerosis, and neurodegenerative disorders. Indeed, we observed increased expression of proinflammatory cytokines by oxidative stress. In the proposed study, we will test the hypothesis that glial cell activation and inflammatory responses during adolescence contribute to altered development of glutamatergic synapses. We will perform in vivo knockdown of GSTT2 expression at specific developmental stages in mice as a model to induce glial cell activation and inflammation via increased oxidative stress. We will characterize the effects of knockdown on the activation of microglia and astrocytes as well as the production of proinflammatory cytokines. We will also assess the effects of knockdown on development of glutamatergic synapses and the expression of synaptic/dendritic immune molecules. Finally, we will address the role of innate immune signaling in microglia by using microglia-specific deletion of MyD88, a molecule that plays a central role in innate immune signaling. The training and research proposal will enable the candidate to develop into an independent investigator in neuropsychiatry research. The project will contribute to the understanding of the roles for glial cells and inflammation in altered brain development during adolescence relevant to SZ.

项目总结/摘要 青春期脑发育障碍可能是精神分裂症（SZ）的基础。尽管许多 报道显示在SZ中没有观察到星形胶质细胞增生，积累的证据表明， 星形胶质细胞和小胶质细胞以及异常免疫/炎症反应也可能是SZ的基础。 尽管如此，目前还不清楚神经胶质细胞和炎症是否或在多大程度上参与了大脑的改变， 青春期的发展。最近，我们发现免疫/应激相关的表达， 基因在来源于SZ患者的活神经元细胞中改变。受影响最大的基因包括谷胱甘肽 S-transferase theta 2（GSTT2）基因，其调节细胞解毒系统并保护细胞免受 活性氧代谢物氧化应激激活先天免疫信号传导，并有助于 在各种疾病如糖尿病、动脉粥样硬化和神经退行性疾病中的炎症。的确， 我们观察到氧化应激引起的促炎细胞因子表达增加。在拟议的研究中， 我们将检验青春期的胶质细胞激活和炎症反应 神经元突触发育的改变我们将在体内敲低GSTT2表达， 在小鼠中的特定发育阶段作为模型，通过增加 氧化应激我们将描述敲除对小胶质细胞和星形胶质细胞活化的影响， 以及促炎细胞因子的产生。我们还将评估击倒对 神经元能突触的发育和突触/树突免疫分子的表达。最后， 我们将通过使用MyD88的小胶质细胞特异性缺失， 一种在先天免疫信号传导中起核心作用的分子。培训和研究建议将使 成为神经精神病学研究的独立调查员的候选人。该项目将 有助于理解神经胶质细胞和炎症在大脑发育过程中的作用， 与SZ相关的青春期。