Pyramidal neuron hypoactivity in schizophrenia cortex
精神分裂症皮质锥体神经元活性低下
基本信息
- 批准号:10452726
- 负责人:
- 金额:$ 8.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAddressAffectAllelesAnimalsAntibodiesAntipsychotic AgentsAutopsyBehaviorBehavioralBinding ProteinsBiological AssayBiological MarkersBloodBlood - brain barrier anatomyBrainCREB1 geneCandidate Disease GeneCarrier ProteinsCell Culture TechniquesCognitive deficitsCollectionConflict (Psychology)CopperDataData CollectionDelusionsDemyelinationsDiseaseDopamineDopamine-beta-monooxygenaseDrug TargetingEducational process of instructingElectron MicroscopyEpigenetic ProcessExhibitsFamilyFiberFoundationsFutureGenesGeneticGenotypeGoalsHallucinationsHippocampus (Brain)HomeostasisHypermethylationImmunohistochemistryImpaired cognitionImpairmentIndividualKnock-outKnockout MiceKnowledgeLearningLearning SkillLinkMAP Kinase GeneMediatingMediationMental disordersMentorsMessenger RNAMetabolismMethylationMidbrain structureMitochondriaMolecularMusNeuraxisPathologyPathway interactionsPatientsPeripheralPersonsPopulationProtein DeficiencyProtein IsoformsProteinsRegulationResearchResearch PersonnelReverse Transcriptase Polymerase Chain ReactionRoleSchizophreniaStarvationSubstantia nigra structureSymptomsSystemTechniquesTestingTissuesVariantWestern BlottingWild Type MouseWritingbehavioral impairmentbrain volumecognitive functiondrug developmentdystrobrevinemerging adultexperimental studygene therapygenetic varianthigh riskhippocampal pyramidal neuronhypocupremiainterestlearning progressionmeetingsmonoaminemouse modelmultidisciplinarymyelinationnew therapeutic targetnovel markerpreadolescencepromoterprotein expressionquetiapinerisk variantskillsstemwhite matter
项目摘要
Schizopphrenia (SZ) affects 1% of the world population. Allelic variants of the dystrobrevin binding protein
1 (DTNBP1) gene, now a top SZ candidate gene, are associated with fiber tract impairments in healthy people
and reduced brain volume in preteens- both SZ symptoms. However, the downstream effects of decreased
dysbindin are poorly understood. Dysfunctional dysbindin decreases the copper-transporting P-type ATPase
(ATP7A) and the copper transporter CTR1. ATP7A and CTR1 facilitate copper transport between the blood
and the brain. The role of copper in SZ has been controversial, with many studies finding increased blood
copper in patients. However, these studies have not considered copper may build up in the blood because it
cannot get into the brain. Copper-decreasing experimental manipulations produce demyelination, dopamine
increases, and SZ-like behavioral impairments. Taken together, dysbindin/copper alterations can result in SZ-
like pathology such as impaired white matter integrity, excess dopamine, and altered mitochondrial activity,
and yet this combined pathway remains largely unstudied. Overall, I hypothesize copper transport alterations
contribute to SZ pathology, potentially through decreased dysbindin expression. I will test this in postmortem
SZ brain, first-episode antipsychotic-naïve SZ patients, and a dysbindin knockout mouse model.
Specific Aim 1: I have learned western blotting, and am now learning immunohistochemical analysis.
Specific Aim 2A. We will test the copper state of postmortem substantia nigra and hippocampus, and the
relationship of this state to copper transporters ATP7A/CTR1 in both treated and untreated SZ. Furthermore,
we will assess the mechanism of action of antipsychotics in relation to these variables.
Specific Aim 2B. To discover potential schizophrenia biomarkers, we will assess peripheral copper state
and its relationship to copper transporters and methylation status of DTNBP1, SLC31A1(CTR1), and ATP7A
before and after 6 weeks of antipsychotic treatment in first-episode, antipsychotic-naïve SZ patients.
Specific Aim 2C. In dysbindin knockout, heterozygous, and wild-type mice, we will test peripheral,
hippocampal, and nigral copper state, and the relation to copper transporters ATP7A/CTR1, cognitive deficits,
and the mechanism of antipsychotic mediated changes before and after 28 days quetiapine treatment.
Specific Aim 3: These studies will provide the first evidence of SZ brain copper state, and resolve the
juxtaposition between excess copper in SZ blood and the SZ-like symptoms induced by copper deficit.
Furthermore, these studies will provide new data about risk gene dysbindin and its effects on copper
transporters (a previously unstudied pathway in SZ) and a potential mechanism of antipsychotic rescue of
copper starvation deficits, which could yield novel targets for drug development. I will learn quantitative RT-
PCR, methylation assay, immunohistochemistry, electron microscopy and tissue sectioning, brain collection,
scientific writing, lab and animal management, and all that these skills entail, as well as proficient teaching.
精神分裂症(SZ)影响着世界上1%的人口。肌营养不良蛋白结合蛋白的等位变异
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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Kirsten Schoonover其他文献
Kirsten Schoonover的其他文献
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{{ truncateString('Kirsten Schoonover', 18)}}的其他基金
Pyramidal neuron hypoactivity in schizophrenia cortex
精神分裂症皮质锥体神经元活性低下
- 批准号:
10012945 - 财政年份:2019
- 资助金额:
$ 8.78万 - 项目类别:
Pyramidal neuron hypoactivity in schizophrenia cortex
精神分裂症皮质锥体神经元活性低下
- 批准号:
10226029 - 财政年份:2019
- 资助金额:
$ 8.78万 - 项目类别:
Mechanisms of Dysbindin Abnormalities in Schizophrenia
精神分裂症中 Dysbindin 异常的机制
- 批准号:
9470628 - 财政年份:2017
- 资助金额:
$ 8.78万 - 项目类别:
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