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
• 负责人: Kirsten Schoonover
• 金额: $ 8.78万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10226029
• 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; hippocampal pyramidal neuron; 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.

精神病（SZ）影响世界人口的1％。双胞胎结合蛋白的等位基因变体 1（DTNBP1）基因，现在是最高的SZ候选基因，与健康人的纤维道障碍有关 并减少了Preteens-两个SZ符号的大脑体积。但是，下游的效果下降了 诱发障碍知之甚少。功能障碍的功能障碍可降低铜运输P型ATPase （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中的作用引起了争议，许多研究发现血液增加 患者的铜。但是，这些研究尚未考虑铜可能会在血液中积聚 无法进入大脑。铜降低实验操作会产生脱髓鞘，多巴胺 增加和类似SZ的行为障碍。综上 像病理（例如白质完整性受损，超过多巴胺）和线粒体活性改变一样， 然而，这种组合的途径在很大程度上仍然没有被研究。总体而言，我假设铜运输变化 有助于SZ病理学，有可能通过降低的胞质素表达来促进。我将在术后测试 SZ脑，第一集抗精神病药 - 不接受SZ患者和dysbindin敲除小鼠模型。 具体目的1：我已经学习了蛋白质印迹，现在正在学习免疫组织化学分析。 特定目标2a。我们将测试Nigra和Hippocampus的铜铜状态，以及 该状态与经过处理和未处理的SZ中的铜转运蛋白ATP7A/CTR1的关系。此外， 我们将评估与这些变量有关的抗精神病药作用机理。 特定目标2B。为了发现潜在的精神分裂症生物标志物，我们将评估外围铜状态 及其与DTNBP1，SLC31A1（CTR1）和ATP7A的铜转运蛋白的关系和甲基化状态 在第一期，抗精神病药 - 未经SZ患者的抗精神病药物治疗之前和之后进行了6周之前和之后。 特定目标2C。在Dysbindin敲除，杂合子和野生型小鼠中，我们将测试外围 海马和ni铜状态，以及与铜转运蛋白ATP7A/CTR1的关系，认知定义 以及28天喹硫平治疗前后抗精神病药的机制。 特定目的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防御引起的SZ样症状之间的并置。 此外，这些研究将提供有关风险基因dysbindin及其对铜的影响的新数据 转运蛋白（SZ中以前未研究的途径）和抗精神病药的潜在机制 铜饥饿定义了，这可能会产生用于药物开发的新目标。我将学习定量的RT- PCR，甲基化测定，免疫组织化学，电子显微镜和组织切片，大脑收集， 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。