Project-004
项目-004
基本信息
- 批准号:10686445
- 负责人:
- 金额:$ 69.15万
- 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 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdolescenceAdolescentAdolescent DevelopmentAdultAstrocytesAutopsyBasal GangliaBehaviorBehavioralBiologicalBiological AssayBiological ModelsBiologyBrainBrain regionCD47 geneCallithrixCell modelCellsCellular AssayCognitionCognitiveComplementComplement component C4Complement component C4aComplexDecision MakingDevelopmentDiseaseDistantEnvironmentEnvironmental Risk FactorEtiologyFunctional disorderGene ExpressionGenerationsGenesGeneticGenetic RiskGenetic TranscriptionGenomicsGoalsHumanImmuneImmunologyIncidenceIndividualInterventionInvestigationLinkMapsMediatingMental HealthMental disordersModelingMolecularMultimediaMusNeuroanatomyNeurodevelopmental DisorderNeuroimmuneNeuroimmunomodulationNeuronsNeurosciencesOutcomeParentsPathway interactionsPersonsPharmacologyPhenotypePhysiologicalPhysiologyPlayPopulationResearchResearch PersonnelResourcesRewardsRiskRisk AssessmentRisk FactorsRoleRouteSamplingSchizophreniaShapesSignal TransductionSocial BehaviorSocial WorkersSourceSpecificitySynapsesTestingThalamic structureTherapeuticTissue ModelTrainingWorkadolescent brain developmentbehavioral phenotypingbrain tissuecell typechildhood adversitycognitive developmentcourse developmentcritical periodfrontal lobehuman stem cellshuman tissueinnovationinterdisciplinary collaborationinterestmembermouse modelneuropsychiatrynon-geneticnonhuman primatenovelnovel diagnosticsnovel strategiesnovel therapeutic interventionoutreachoverexpressionpostnatalpsychiatric symptompsychogeneticsrelating to nervous systemresponserisk variantschizophrenia risksocialsymposiumsynaptic functionsynaptic pruningsynaptogenesisteachertherapeutic evaluationtooltraining opportunitytranscriptomevulnerable adolescentweb siteyoung adult
项目摘要
The pathophysiology of schizophrenia has been unknown, resulting in a lack of innovative
therapeutics with novel mechanisms of action. The Conte Center for Neuroimmune Studies was
created to build on our discovery that the biology underlying the most significant schizophrenia
common genetic risk variants involves neuroimmune mechanisms of synaptic pruning. We have
found that risk variants of the complement component C4 genes are correlated with increased
C4A expression in the brain and CSF, and that overexpression of human C4A in a mouse model
results in excess synaptic pruning and social behavioral deficits. We have further shown that
additional neuroimmune molecules encoded at schizophrenia risk loci, CD47 and CSMD1,
influence synaptic pruning and complement activity. Lastly, schizophrenia is unusual among
neurodevelopmental disorders in its late-adolescent/early-adult onset, and childhood adversity is
a major non-genetic risk factor for schizophrenia; yet the biological underpinnings of adolescent
psychiatric vulnerability are wholly unknown. We have identified a critical period of circuit
refinement in the mouse frontal cortex that we propose can be exploited to better understand the
unique vulnerability of adolescent brain development to psychiatric risk factors.
The goals of the Center in our next five years are to both deepen the focus on C4-mediated
synaptic pruning as a pathophysiological mechanism, and expand the scope of our investigations
to create a fuller picture of neuroimmune pathways, their upstream regulators, their cellular
effectors, and their downstream circuit-level and behavioral impacts. Project 1 will investigate the
role of astrocytes, the main source of C4 in the brain, by manipulating schizophrenia risk genes
in these cells and assaying the impacts on synapse formation and function. Project 2 will spatially
map the brain’s transcriptional response to C4 overexpression, and test the therapeutic
hypothesis that inhibition of C4 activity may rescue over-pruning and associated behavioral
phenotypes. Project 3 will examine the circuit specificity of the adolescent critical period, the
impacts of gene-by-environment risk factor interactions, and the roles of the brain borders. Project
4 will explore circuit-level interactions between the basal ganglia and frontal cortex in the context
of adolescent development, psychiatric risk factors, and risk/reward decision-making. We will also
lay the groundwork for expanding neuroimmune studies of psychiatric risk to a non-human
primate model, the marmoset. Finally, our Administrative Core will facilitate interdisciplinary
collaboration that exploits the full range of expertise across the four labs, and coordinate outward-
facing activities including the annual research symposium.
精神分裂症的病理生理机制一直不清楚,导致缺乏创新
具有新作用机制的治疗学。康特神经免疫研究中心是
是基于我们的发现而创建的,即最重要的精神分裂症背后的生物学
常见的遗传风险变异涉及突触修剪的神经免疫机制。我们有
发现补体成分C4基因的风险变异与增加相关
C4a在脑和脑脊液中的表达,以及在小鼠模型中人类C4a的过表达
会导致过度的突触修剪和社会行为缺陷。我们已经进一步表明,
精神分裂症危险基因CD47和CSMD1上编码的其他神经免疫分子,
影响突触修剪和补体活性。最后,精神分裂症在
青春期晚期/成年早期的神经发育障碍,儿童时期的逆境
精神分裂症的主要非遗传风险因素;然而青少年的生物学基础
精神上的脆弱性是完全未知的。我们已经确定了一个关键的巡回周期
我们提出的小鼠额叶皮质的精细化可以被用来更好地理解
青少年大脑发育对精神危险因素的独特脆弱性。
该中心未来五年的目标是深化对C4中介的关注
突触修剪作为一种病理生理机制,并扩大了我们的研究范围
为了更全面地了解神经免疫途径,它们的上游调节因子,它们的细胞
效应器及其下游电路级和行为影响。项目1将调查
大脑中C4的主要来源--星形胶质细胞通过操纵精神分裂症危险基因所起的作用
并分析其对突触形成和功能的影响。项目2将在空间上
绘制大脑对C4过度表达的转录反应图,并测试治疗
C4活性抑制可能挽救过度修剪和相关行为的假说
表型。项目3将检查青少年关键期的电路特异性,即
基因与环境风险因素相互作用的影响,以及大脑边界的作用。项目
4将在此背景下探索基底神经节和额叶皮质之间的电路水平相互作用
青少年发展、精神风险因素和风险/回报决策。我们还将
为将精神疾病风险的神经免疫研究扩展到非人类奠定基础
灵长类动物模型,绒猴。最后,我们的行政核心将促进跨学科
协作利用四个实验室的所有专业知识,并向外协调-
面向包括年度研究研讨会在内的活动。
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:
$ 69.15万 - 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:
$ 69.15万 - 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:
$ 69.15万 - 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:
$ 69.15万 - 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:
$ 69.15万 - 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:
$ 69.15万 - 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:
$ 69.15万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 69.15万 - 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:
$ 69.15万 - 项目类别:
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