Molecular mechanisms of abnormal dendritic spine plasticity in schizophrenia
精神分裂症树突棘可塑性异常的分子机制
基本信息
- 批准号:8608434
- 负责人:
- 金额:$ 65.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-02-20 至 2017-01-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdolescentAffectAmino AcidsAutistic DisorderBiological ModelsBrainBrain imagingCell modelCell physiologyCerebral cortexCodeCognitionCognitiveCognitive deficitsConfocal MicroscopyDataDendritic SpinesDiseaseElectroporationExcitatory SynapseExonsGenesGlutamate ReceptorGlutamatesHeritabilityHuman GeneticsImageIndividualKnowledgeMeasuresMediatingModelingMolecularMorphologyMusMutationNRG1 geneNeurobiologyNeuronsPathogenesisPathway interactionsPatientsPhenotypeProteinsReportingResearchSchizophreniaSiblingsStructureSusceptibility GeneSynapsesSynaptic TransmissionTestingTherapeutic InterventionThickValidationVariantVertebral columnbasedensityfrontal lobegray matterhuman subjectin uteroinsightmouse modelmultidisciplinarynovelpeerprotein functionrare varianttherapeutic targettranslational approachtwo-photon
项目摘要
DESCRIPTION (provided by applicant): Multiple lines of evidence support a key role for abnormal synaptic connectivity in schizophrenia, but the molecular mechanisms underlying its pathogenesis are not known. Understanding these mechanisms may allow us to identify new targets for therapeutic intervention, especially early in the course of illness. The application wil focus on dendritic spines as cellular substrates of brain connectivity, because the majority of excitatory synapses are located on spines, and reduced spine density has been extensively documented in schizophrenia. Mounting evidence indicating that known schizophrenia susceptibility genes regulate spines and that regulators of spine plasticity are implicated in schizophrenia, strongly support the model that perturbations in the molecular network underlying spine plasticity are critically involved in the pathogenesis of schizophrenia. However, the mechanisms through which genetic alterations in this network underlie specific neurobiological phenotypes related to schizophrenia are not known. Recent data indicates that rare variants (including amino acid mutations) cumulatively account for a significant fraction of the "missing heritability" in schizophrenia, and cluster in gene networks that control synapses. Because a large fraction of such mutations are estimated to impair protein function, many are expected to cause brain circuit alterations. Thus, we propose that by identifying, testing for association, and characterizing rare variants enriched in schizophrenia, we will provide critical new insights into disease pathogenesis, because such mutations provide detailed knowledge about the affected molecular and cellular functions. Based on our preliminary data, we hypothesize that rare coding variants in genes that control dendritic spine plasticity, cumulativel enriched in subjects with schizophrenia, disrupt cortical connectivity and impact neuromorphological and cognitive measures in carriers. Using a multidisciplinary translational approach that combines human genetics, molecular and electrophysiological studies in cellular models, functional validation in mice, and cognitive assessment and structural brain imaging in patients, we will pursue these specific aims: 1) To assess the cellular impact of mutations in spine plasticity genes identified in schizophrenia subjects. 2) To determine the impact of mutations in spine plasticity genes on glutamatergic synaptic transmission. 3) To determine the impact of mutations in spine plasticity genes on cortical ultrastructure and functional connectivit in mice. 4) To assess the relationships between mutations in spine plasticity genes and phenotypic measures in patients.
描述(由申请人提供):多个证据支持精神分裂症异常突触连通性的关键作用,但是尚不清楚其发病机理的分子机制。了解这些机制可能使我们能够确定治疗干预的新目标,尤其是在疾病的早期。由于大多数兴奋性突触位于棘突上,因此将其关注树突状刺作为大脑连通性的细胞底物,并且在精神分裂症中已广泛记录了脊柱密度的降低。越来越多的证据表明,已知的精神分裂症敏感性基因调节棘突,并且脊柱可塑性的调节剂与精神分裂症有关,强烈支持该模型,即脊柱可塑性的分子网络中的扰动与精神分裂症的病原体有关。然而,尚不清楚与精神分裂症有关的特定特定神经生物学表型的基础遗传改变的机制。最近的数据表明,罕见的变体(包括氨基酸突变)累积地解释了精神分裂症中“缺失遗传力”的很大一部分,并且在控制突触的基因网络中群集。由于估计很大一部分此类突变会损害蛋白质功能,因此预计许多突变会导致脑电路改变。因此,我们提出,通过鉴定,测试关联并表征富含精神分裂症的稀有变体,我们将对疾病发病机理提供关键的新见解,因为这种突变提供了有关影响分子和细胞功能的详细知识。根据我们的初步数据,我们假设在控制树突状脊柱可塑性的基因中,稀有的编码变体富含精神分裂症受试者,破坏皮质连通性以及载体中神经形态和认知测量的累积。使用结合人类遗传学,细胞模型中的分子和电生理研究,小鼠的功能验证以及患者的认知评估和结构性脑成像的多学科翻译方法,我们将追求这些特定目的:1)评估脊柱可塑性基因突变的细胞影响。 2)确定脊柱可塑性基因突变对谷氨酸能突触传播的影响。 3)确定脊柱可塑性基因对小鼠皮质超微结构和功能连接的影响。 4)评估脊柱可塑性基因突变与患者表型测量之间的关系。
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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Peter Penzes其他文献
Peter Penzes的其他文献
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{{ truncateString('Peter Penzes', 18)}}的其他基金
Neuronal excitability and copy number variation disorders
神经元兴奋性和拷贝数变异障碍
- 批准号:
10039790 - 财政年份:2020
- 资助金额:
$ 65.25万 - 项目类别:
Neuronal excitability and copy number variation disorders
神经元兴奋性和拷贝数变异障碍
- 批准号:
10250497 - 财政年份:2020
- 资助金额:
$ 65.25万 - 项目类别:
Neuronal excitability and copy number variation disorders
神经元兴奋性和拷贝数变异障碍
- 批准号:
10407640 - 财政年份:2020
- 资助金额:
$ 65.25万 - 项目类别:
Neuronal excitability and copy number variation disorders
神经元兴奋性和拷贝数变异障碍
- 批准号:
10626765 - 财政年份:2020
- 资助金额:
$ 65.25万 - 项目类别:
Adhesion molecules and developmental epilepsy disorders
粘附分子与发育性癫痫病
- 批准号:
10592736 - 财政年份:2017
- 资助金额:
$ 65.25万 - 项目类别:
Molecular mechanisms of abnormal dendritic spine plasticity in schizophrenia
精神分裂症树突棘可塑性异常的分子机制
- 批准号:
8287503 - 财政年份:2012
- 资助金额:
$ 65.25万 - 项目类别:
Synaptic and dendritic dysfunction in psychiatric disorders
精神疾病中的突触和树突功能障碍
- 批准号:
9402750 - 财政年份:2012
- 资助金额:
$ 65.25万 - 项目类别:
Molecular mechanisms of abnormal dendritic spine plasticity in schizophrenia
精神分裂症树突棘可塑性异常的分子机制
- 批准号:
8605620 - 财政年份:2012
- 资助金额:
$ 65.25万 - 项目类别:
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