Mechanisms of Dysbindin Abnormalities in Schizophrenia

精神分裂症中 Dysbindin 异常的机制

• 批准号: 9470628
• 负责人: Kirsten Schoonover
• 金额: $ 3.65万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-28 至 2019-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9470628
• 关键词: ATP phosphohydrolase; Address; Affect; Alleles; Animals; Antibodies; Antipsychotic Agents; Autopsy; Behavior; Behavioral; Binding Proteins; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; CREB1 gene; Candidate Disease Gene; Carrier Proteins; Cell Culture Techniques; Cognitive deficits; Collection; Conflict (Psychology); Copper; Data; Data Collection; Delusions; Demyelinations; Disease; Dopamine; Dopamine-beta-monooxygenase; Drug Targeting; Educational process of instructing; Electron Microscopy; Epigenetic Process; Exhibits; Family; Fiber; Foundations; Future; Genes; Genetic; Genotype; Goals; Hallucinations; Hippocampus (Brain); Homeostasis; Hypermethylation; Immunohistochemistry; Impaired cognition; Impairment; Individual; Knock-out; Knockout Mice; Knowledge; Learning; Learning Skill; Link; MAP Kinase Gene; Mediating; Mediation; Mental disorders; Mentors; Messenger RNA; Metabolism; Methylation; Midbrain structure; Mitochondria; Molecular; Mus; Neuraxis; Pathology; Pathway interactions; Patients; Peripheral; Population; Protein Deficiency; Protein Isoforms; Proteins; Regulation; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Schizophrenia; Starvation; Substantia nigra structure; Symptoms; System; Techniques; Testing; Tissues; Variant; Western Blotting; Wild Type Mouse; Writing; behavioral impairment; brain volume; cognitive function; drug development; dystrobrevin; emerging adult; experimental study; gene therapy; genetic variant; high risk; hypocupremia; interest; learning progression; meetings; monoamine; mouse model; multidisciplinary; myelination; new therapeutic target; novel marker; preadolescence; promoter; protein expression; quetiapine; risk variant; skills; stem; white matter

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.

裂孔症(SZ)影响着世界1%的人口。营养不良蛋白结合蛋白的等位基因变体 1(DTNBP1)基因，现在是SZ的首选候选基因，与健康人的纤维束损伤有关 以及青春期前的大脑体积缩小--这两种症状都是SZ症状。然而，下游的影响减少了 人们对异常结合蛋白知之甚少。功能障碍结合蛋白降低铜转运P型ATPase (ATP7A)和铜运输商CTR1.ATP7A和CTR1促进铜在血液之间的运输 还有大脑。铜在SZ中的作用一直存在争议，许多研究发现血液增加 病人体内的铜。然而，这些研究没有考虑到铜可能会在血液中积聚，因为它 无法进入大脑。减少铜的实验操作产生脱髓鞘，多巴胺 增加，以及类似SZ的行为障碍。综上所述，结合障碍/铜蚀变可导致SZ- 就像病理一样，白质完整性受损，多巴胺过量，线粒体活动改变， 然而，这种结合的途径在很大程度上仍未得到研究。总体而言，我假设铜运输发生了变化 在SZ病理中起重要作用，可能通过降低dybindin的表达。我会在尸检中检验这一点 SZ脑，首发抗精神病药物天真的SZ患者，以及一个结合障碍基因敲除小鼠模型。 具体目标1：我已经学习了免疫印迹，现在正在学习免疫组织化学分析。 具体目标2 A。我们将测试死后黑质和海马体的铜状态，以及 在处理和未处理的深圳，这种状态与铜转运体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记物，我们将评估外周血铜状态 及其与铜转运蛋白及DTNBP1、SLC31A1(CTR1)和ATP7A甲基化状态的关系 首发、未服用抗精神病药物的SZ患者在6周的抗精神病药物治疗前和治疗后。 具体目标2C。在dybindin基因敲除、杂合子和野生型小鼠中，我们将测试外周血细胞， 海马铜和黑质铜状态及其与铜转运体ATP7A/CTR1的关系，认知障碍， 以及奎硫平治疗28天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血中铜过多与缺铜所致的SZ样症状并存。 此外，这些研究还将提供有关危险基因异常结合素及其对铜的影响的新数据。 转运体(以前在深圳未被研究的途径)和抗精神病药物救援的潜在机制 铜饥饿不足，这可能为药物开发产生新的目标。我会学习定量RT- 聚合酶链式反应，甲基化分析，免疫组织化学，电子显微镜和组织切片，脑收集， 科学写作、实验室和动物管理，以及所有这些技能，以及熟练的教学。