Neural-immune mechanisms and synaptic connectivity in psychiatric illness

精神疾病中的神经免疫机制和突触连接

• 批准号: 9280281
• 负责人: Michael Craig Carroll
• 金额: $ 200万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280281
• 关键词: Adolescent; Adult; Affect; Age of Onset; Alleles; Animal Model; Behavior; Biological Process; Brain; Cells; Collaborations; Complement; Complement 4b; Complement component C4a; Computer Analysis; Data; Data Set; Development; Disease; Employee Strikes; Environment; Event; Family health status; Future; Gene Expression; Genes; Genetic Risk; Genome; Genomics; Goals; Human; Human Biology; Human Genetics; Human Genome; Immune; Immunology; Individual; Interdisciplinary Study; Knowledge; Maps; Mediating; Medical; Mental disorders; Microglia; Mission; Modeling; Molecular; Mus; Neurons; Neurosciences; Pathway interactions; Peripheral; Population; Postdoctoral Fellow; Process; Protocols documentation; Public Health; Regulation; Research; Research Personnel; Resolution; Resources; Risk; Schizophrenia; Science; Scientist; Series; Shapes; Statistical Data Interpretation; Synapses; Vitronectin; Work; association cortex; brain behavior; cost; critical period; data sharing; genetic approach; genetic variant; genome-wide; genome-wide analysis; graduate student; innovation; meetings; mouse model; neuropsychiatric disorder; neuropsychiatry; novel; novel therapeutic intervention; novel therapeutics; postnatal; relating to nervous system; symposium; synaptic pruning; training opportunity; undergraduate student

The pathophysiological processes underlying neuropsychiatric disorders have been unknown; as a result, these disorders have lacked innovative medical therapies with new mechanisms of action. We recently identified the alleles underlying the human genome's largest population-level influence on risk of schizophrenia – a series of structural alleles of the complement C4A and C4B genes, each of which appears to affect schizophrenia risk in proportion to the amount of C4A expression it generates in the brain. We also found that C4 shapes synaptic refinement in a mouse model of postnatal activity-dependent synapse elimination. These findings may help explain known features of schizophrenia, including reduced numbers of synapses in key cortical regions and an adolescent age of onset that corresponds with developmentally timed waves of synaptic pruning in these regions. The goal of the work we envision for a Conte Center is to develop our understanding of neural-immune interactions and synapses while also generating novel scientific resources that can be used to evaluate current and future hypotheses about schizophrenia-implicated genes, neural-immune interactions, and critical periods for synaptic refinement. Our proposed work arises from close, successful collaboration of scientists with expertise in genomics, immunology, and neuroscience. We aim to accomplish our Center's missions through scientific projects and cores. Project 1 will seek to understand how CNS cells regulate the expression of complement and reprogram gene expression as they traverse critical periods in the maturation of their circuits. Project 2 will create mice that carry human C4 genes and alleles; examining how human C4 allelic diversity and expression levels affect microglia-mediated synaptic pruning and other processes. Project 3 will reveal the functional consequences of complement-cascade dysregulation – both over- and under-pruning – on circuit function and behavior. A Computational and Statistical Analysis Core will contribute to research in all three projects by facilitating analyses of genome-wide expression data and genome sequence data. An administrative core will coordinate biweekly lab meetings and outward-facing activities, including an annual symposium on emerging research at the interface of neuroscience, immunology and genomics. We hope to advance the search for molecular understanding of schizophrenia while advancing the understanding of brain development, the interacting influences of genes and environment on brain and behavior, and possibly general principles that could be applicable to the mechanisms and pathways that go awry in other mental illnesses.

神经精神疾病的病理生理过程尚不清楚；因此， 这些疾病缺乏具有新作用机制的创新医学疗法。我们最近 确定了人类基因组中对精神分裂症风险最大的人群水平影响的等位基因 – 补体 C4A 和 C4B 基因的一系列结构等位基因，每个基因似乎都会影响 精神分裂症的风险与其在大脑中产生的 C4A 表达量成正比。我们还发现 C4 在出生后活动依赖性突触消除的小鼠模型中塑造突触细化。这些 研究结果可能有助于解释精神分裂症的已知特征，包括关键部位突触数量的减少 皮质区域和青春期发病年龄与发育时间波相对应 这些区域的突触修剪。 我们设想 Conte 中心的工作目标是加深我们对神经免疫的理解 相互作用和突触，同时还产生可用于评估当前的新颖的科学资源 以及关于精神分裂症相关基因、神经免疫相互作用和关键期的未来假设 用于突触细化。我们提出的工作源于科学家们的密切、成功的合作 基因组学、免疫学和神经科学方面的专业知识。我们的目标是通过以下方式完成中心的使命 科学项目和核心。项目 1 将寻求了解中枢神经系统细胞如何调节 当它们经历其电路成熟的关键时期时，互补并重新编程基因表达。 项目2将培育携带人类C4基因和等位基因的小鼠；检查人类 C4 等位基因多样性如何 表达水平影响小胶质细胞介导的突触修剪和其他过程。项目 3 将揭示 补体级联失调的功能后果（过度修剪和修剪不足）对电路的影响 功能和行为。计算和统计分析核心将为这三个方面的研究做出贡献 通过促进全基因组表达数据和基因组序列数据的分析来开展项目。一个 行政核心将协调每两周一次的实验室会议和对外活动，包括年度活动 关于神经科学、免疫学和基因组学交叉领域的新兴研究的研讨会。 我们希望在推动精神分裂症分子生物学研究的同时 了解大脑发育、基因和环境对大脑的相互作用影响 行为，以及可能适用于发生的机制和途径的一般原则 导致其他精神疾病。