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) 影响着世界人口的 1%。抗坏血酸结合蛋白的等位基因变体
1 (DTNBP1) 基因目前是 SZ 的顶级候选基因,与健康人的纤维束损伤有关
青春期前的脑容量减少——这都是精神分裂症的症状。然而,下游影响减弱
人们对dysbindin知之甚少。功能失调的 Dysbindin 会降低铜转运 P 型 ATP 酶
(ATP7A) 和铜转运蛋白 CTR1。 ATP7A 和 CTR1 促进血液之间的铜转运
和大脑。铜在 SZ 中的作用一直存在争议,许多研究发现增加血液
患者体内的铜。然而,这些研究并没有考虑到铜可能会在血液中积聚,因为它
无法进入大脑。减少铜的实验操作会产生脱髓鞘、多巴胺
增加,以及类似 SZ 的行为障碍。综上所述,dysbindin/铜的改变可导致 SZ-
例如白质完整性受损、多巴胺过多和线粒体活性改变等病理学,
然而,这种组合途径在很大程度上仍未得到研究。总的来说,我假设铜的运输发生了变化
可能通过减少 Dysbindin 表达来促进 SZ 病理。我将在事后测试这一点
SZ 大脑、首次接受抗精神病药物治疗的 SZ 患者以及 Dysbindin 敲除小鼠模型。
具体目标1:我已经学习了蛋白质印迹,现在正在学习免疫组化分析。
具体目标 2A。我们将测试死后黑质和海马体的铜状态,以及
在处理和未处理的 SZ 中,这种状态与铜转运蛋白 ATP7A/CTR1 的关系。此外,
我们将评估与这些变量相关的抗精神病药物的作用机制。
具体目标 2B。为了发现潜在的精神分裂症生物标志物,我们将评估外周铜状态
及其与铜转运蛋白和 DTNBP1、SLC31A1(CTR1) 和 ATP7A 甲基化状态的关系
首发、未接受抗精神病药物治疗的 SZ 患者接受抗精神病药物治疗 6 周之前和之后。
具体目标 2C。在 Dysbindin 敲除、杂合和野生型小鼠中,我们将测试外周、
海马和黑质铜状态,以及与铜转运蛋白 ATP7A/CTR1、认知缺陷、
以及 28 天喹硫平治疗前后抗精神病药物介导的变化机制。
具体目标 3:这些研究将提供 SZ 脑铜状态的第一个证据,并解决
SZ 血液中过量的铜与铜缺乏引起的 SZ 样症状并存。
此外,这些研究将提供有关风险基因失调及其对铜的影响的新数据
转运蛋白(深圳以前未研究过的途径)和抗精神病药物救援的潜在机制
铜匮乏,这可能会产生药物开发的新目标。我将学习定量RT-
PCR、甲基化测定、免疫组织化学、电子显微镜和组织切片、脑采集、
科学写作、实验室和动物管理,以及所有这些技能所需要的,以及熟练的教学。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Kirsten Schoonover其他文献
Kirsten Schoonover的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 8.78万 - 项目类别:
Research Grant