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
基本信息
- 批准号:9280281
- 负责人:
- 金额:$ 200万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdolescentAdultAffectAge of OnsetAllelesAnimal ModelBehaviorBiological ProcessBrainCellsCollaborationsComplementComplement 4bComplement component C4aComputer AnalysisDataData SetDevelopmentDiseaseEmployee StrikesEnvironmentEventFamily health statusFutureGene ExpressionGenesGenetic RiskGenomeGenomicsGoalsHumanHuman BiologyHuman GeneticsHuman GenomeImmuneImmunologyIndividualInterdisciplinary StudyKnowledgeMapsMediatingMedicalMental disordersMicrogliaMissionModelingMolecularMusNeuronsNeurosciencesPathway interactionsPeripheralPopulationPostdoctoral FellowProcessProtocols documentationPublic HealthRegulationResearchResearch PersonnelResolutionResourcesRiskSchizophreniaScienceScientistSeriesShapesStatistical Data InterpretationSynapsesVitronectinWorkassociation cortexbrain behaviorcostcritical perioddata sharinggenetic approachgenetic variantgenome-widegenome-wide analysisgraduate studentinnovationmeetingsmouse modelneuropsychiatric disorderneuropsychiatrynovelnovel therapeutic interventionnovel therapeuticspostnatalrelating to nervous systemsymposiumsynaptic pruningtraining opportunityundergraduate student
项目摘要
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.
神经精神障碍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
确定了人类基因组对精神分裂症风险影响最大的等位基因
- 补体C4 A和C4 B基因的一系列结构等位基因,其中每一个似乎影响
精神分裂症的风险与其在大脑中产生的C4 A表达量成比例。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
这些发现可能有助于解释精神分裂症的已知特征,包括关键神经元突触数量的减少。
皮质区域和青春期发病年龄,对应于发育定时波,
这些区域的突触修剪。
我们设想的康特中心的工作目标是发展我们对神经免疫的理解,
相互作用和突触,同时也产生新的科学资源,可用于评估当前的
以及未来关于精神分裂症相关基因、神经免疫相互作用和关键期的假设
来完善突触我们提出的工作源于科学家与
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我们中心的使命:
科学项目和核心。项目1将试图了解中枢神经系统细胞如何调节
当它们穿越其回路成熟的关键时期时,补充和重新编程基因表达。
项目2将创造携带人类C4基因和等位基因的小鼠;研究人类C4等位基因多样性
并且表达水平影响小胶质细胞介导的突触修剪和其它过程。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-电路
功能和行为。计算和统计分析核心将有助于所有三个领域的研究
通过促进全基因组表达数据和基因组序列数据的分析,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,包括每年一次的
神经科学、免疫学和基因组学界面新兴研究专题讨论会。
我们希望在推进精神分裂症分子研究的同时,
了解大脑发育,基因和环境对大脑的相互影响,
行为,以及可能适用于机制和途径的一般原则,
在其他精神疾病中表现不佳。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael Craig Carroll其他文献
Michael Craig Carroll的其他文献
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{{ truncateString('Michael Craig Carroll', 18)}}的其他基金
Astrocyte-neuron communication and vulnerability to mental illness
星形胶质细胞-神经元通讯和患精神疾病的脆弱性
- 批准号:
10686440 - 财政年份:2022
- 资助金额:
$ 200万 - 项目类别:
Neuroimmune mechanisms of adolescent brain development and vulnerability
青少年大脑发育和脆弱性的神经免疫机制
- 批准号:
10686442 - 财政年份:2022
- 资助金额:
$ 200万 - 项目类别:
Contributions of human C4A overexpression to schizophrenia pathogenesis.
人类 C4A 过度表达对精神分裂症发病机制的贡献。
- 批准号:
10686441 - 财政年份:2022
- 资助金额:
$ 200万 - 项目类别:
Evolution of autoreactive GC and epitope spreading in lupus
狼疮自身反应性GC和表位扩散的演变
- 批准号:
10736511 - 财政年份:2018
- 资助金额:
$ 200万 - 项目类别:
Evolution of autoreactive GC and epitope spreading in lupus
狼疮自身反应性GC和表位扩散的演变
- 批准号:
10399632 - 财政年份:2018
- 资助金额:
$ 200万 - 项目类别:
Type I interferon-dependent mechanisms of synapse loss in lupus
狼疮突触丢失的 I 型干扰素依赖性机制
- 批准号:
10433932 - 财政年份:2018
- 资助金额:
$ 200万 - 项目类别:
Type I interferon-dependent mechanisms of synapse loss in lupus
狼疮突触丢失的 I 型干扰素依赖性机制
- 批准号:
10196940 - 财政年份:2018
- 资助金额:
$ 200万 - 项目类别:
Astrocyte-neuron communication and vulnerability to mental illness
星形胶质细胞-神经元通讯和患精神疾病的脆弱性
- 批准号:
10693115 - 财政年份:2017
- 资助金额:
$ 200万 - 项目类别:
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