Molecular, Synaptic, and Circuit Basis for Schizophrenia-related Phenotypes
精神分裂症相关表型的分子、突触和回路基础
基本信息
- 批准号:9206919
- 负责人:
- 金额:$ 39.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-02-10 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:ANGPTL2 geneActinsAddressAntipsychotic AgentsAppearanceAtrophicAutistic DisorderBehaviorBehavioralBehavioral SymptomsBiologicalBrain regionCanadaCandidate Disease GeneCardiovascular DiseasesCharacteristicsChronic stressClozapineCodeCognitiveComplexCorticotropin-Releasing HormoneCytoskeletonDISC1 geneDefectDendritic SpinesDevelopmentDiseaseEndocytosisEndosomesEpisodic memoryEtiologyExocytosisFutureGenesGeneticGrantHaloperidolHumanHyperactive behaviorHypersensitivityImageImage AnalysisImpaired cognitionImpairmentIndividualInstructionIntellectual functioning disabilityKnock-outKnockout MiceKnowledgeLeadLong-Term PotentiationMalignant NeoplasmsMapsMediatingMemory impairmentMental disordersMicrofilamentsMissionModelingMolecularMolecular AnalysisMorphogenesisMorphologyMusMutant Strains MiceMutationNatureNeurobiologyNeurohormonesNeuronsOutputPathologicPathway interactionsPhenotypePositioning AttributePreventionProcessProsencephalonPublishingRecoveryRegulationRisk FactorsRoleSchizophreniaShort-Term MemorySignal PathwaySignal TransductionSignaling MoleculeStressStructureSymptomsSynapsesSynaptic ReceptorsSynaptic plasticityTestingTimeUnited StatesUnited States National Institutes of HealthVertebral columnVirusbasebehavioral studyburden of illnesscognitive abilitydesigner receptors exclusively activated by designer drugsexperiencegenetic variantin vivoineffective therapiesinnovationinsightmutant mouse modelneural circuitneuropsychiatric disordernovelnovel strategiespolymerizationpublic health relevancereceptorrelating to nervous systemresponsestatisticstrafficking
项目摘要
DESCRIPTION (provided by applicant): Neuropsychiatric disorders are the leading cause of disease burden in the United States and Canada, far outpacing other maladies such as cardiovascular disease and cancer (WHO statistics). Progress in treating neuropsychiatric disorders is severely hampered by our lack of basic knowledge related to their underlying causes. Defects in dendritic spine morphogenesis, a process regulated by dynamic actin remodeling, is a common feature of these disorders and is also associated with stress, which may precipitate disorders such as schizophrenia. Moreover, it is increasingly clear that disruptions in genes that regulate signaling to excitatory synaptic actin are risk factors for schizophrenia, autism, and intellectual disability. Arp2/3 complex is enriched in dendritic spines and stimulates the formation of branched actin downstream of many genes implicated neuropsychiatric disorders. Recently we published that the conditional loss of Arp2/3 in mice leads to the progressive development of multiple synaptic and behavioral phenotypes relevant to models of schizophrenia. Many of the schizophrenia-related behaviors are normalized by the antipsychotics clozapine and haloperidol. The specific aims of this grant build on these exciting findings to address fundamental questions of how SZ-related phenotypes evolve at the synaptic and circuit level and how this is influenced by chronic stress. We anticipate the results of these aims will bridge our knowledge gap regarding how SZ-like phenotypes emerge in vivo, leading to new future directions for the prevention and possible treatments of the disorder.
描述(由申请人提供):神经精神疾病是美国和加拿大疾病负担的主要原因,远远超过其他疾病,如心血管疾病和癌症(WHO统计数据)。神经精神疾病的治疗进展受到了严重阻碍,因为我们缺乏与其根本原因相关的基本知识。树突棘形态发生的缺陷,动态肌动蛋白重塑调节的过程,是这些疾病的一个共同特征,也与压力,这可能会沉淀疾病,如精神分裂症。此外,越来越清楚的是,调节兴奋性突触肌动蛋白信号的基因的破坏是精神分裂症、自闭症和智力残疾的危险因素。Arp 2/3复合物在树突棘中富集,并刺激许多涉及神经精神疾病的基因下游的分支肌动蛋白的形成。最近,我们发表了小鼠Arp 2/3的条件性缺失导致与精神分裂症模型相关的多种突触和行为表型的进行性发展。许多精神分裂症相关的行为通过抗精神病药物氯氮平和氟哌啶醇而正常化。这项资助的具体目标是建立在这些令人兴奋的发现基础上,以解决SZ相关表型如何在突触和电路水平上进化以及如何受到慢性应激影响的基本问题。我们预计这些目标的结果将弥合我们关于SZ样表型如何在体内出现的知识差距,从而为该疾病的预防和可能的治疗提供新的未来方向。
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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SCOTT H SODERLING其他文献
SCOTT H SODERLING的其他文献
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{{ truncateString('SCOTT H SODERLING', 18)}}的其他基金
Proteomic and Functional Analysis of Presynaptic Physiology and Plasticity
突触前生理学和可塑性的蛋白质组学和功能分析
- 批准号:
10403567 - 财政年份:2021
- 资助金额:
$ 39.25万 - 项目类别:
Proteomic and Functional Analysis of Presynaptic Physiology and Plasticity
突触前生理学和可塑性的蛋白质组学和功能分析
- 批准号:
10276768 - 财政年份:2021
- 资助金额:
$ 39.25万 - 项目类别:
Proteomic and Functional Analysis of Presynaptic Physiology and Plasticity
突触前生理学和可塑性的蛋白质组学和功能分析
- 批准号:
10591544 - 财政年份:2021
- 资助金额:
$ 39.25万 - 项目类别:
Analysis of Inhibitory Synaptic Proteins Associated with Brain Disorders
与脑部疾病相关的抑制性突触蛋白分析
- 批准号:
9367494 - 财政年份:2017
- 资助金额:
$ 39.25万 - 项目类别:
Molecular Analysis of Developmental Brain Disorders Associated with Synaptic Pathology
与突触病理学相关的发育性脑疾病的分子分析
- 批准号:
9891097 - 财政年份:2017
- 资助金额:
$ 39.25万 - 项目类别:
Molecular Analysis of Developmental Brain Disorders Associated with Synaptic Pathology
与突触病理学相关的发育性脑疾病的分子分析
- 批准号:
10585092 - 财政年份:2017
- 资助金额:
$ 39.25万 - 项目类别:
Analysis of Inhibitory Synaptic Proteins Associated with Brain Disorders
与脑部疾病相关的抑制性突触蛋白分析
- 批准号:
10176611 - 财政年份:2017
- 资助金额:
$ 39.25万 - 项目类别:
Molecular, Synaptic, and Circuit Basis for Schizophrenia-related Phenotypes
精神分裂症相关表型的分子、突触和回路基础
- 批准号:
8672933 - 财政年份:2014
- 资助金额:
$ 39.25万 - 项目类别:
Molecular, Synaptic, and Circuit Basis for Schizophrenia-related Phenotypes
精神分裂症相关表型的分子、突触和回路基础
- 批准号:
8800576 - 财政年份:2014
- 资助金额:
$ 39.25万 - 项目类别:
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绘制癌症信号通路的架构
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7692069 - 财政年份:2009
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$ 39.25万 - 项目类别:
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