EPIGENETIC CHANGES IN FRONTAL LOBE OF SCHIZOPHRENICS

精神分裂症患者额叶的表观遗传变化

• 批准号: 7097262
• 负责人: Schahram Akbarian
• 金额: $ 26.98万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097262
• 关键词: NMDA receptors; antipsychotic agents; biological signal transduction; brain mapping; cerebellar cortex; cerebral cortex; chromatin; chromatin immunoprecipitation; frontal lobe /cortex; gene expression; genetic promoter element; genetic transcription; genetically modified animals; histones; human tissue; laboratory mouse; messenger RNA; methylation; microarray technology; nucleosomes; pharmacokinetics; polymerase chain reaction; postmortem; prefrontal lobe /cortex; receptor expression; schizophrenia

DESCRIPTION (provided by applicant): Dysfunction of the prefrontal cortex (PFC) is thought to play a key role in the neurobiology of schizophrenia. In particular, the deficit syndrome which includes a subset of negative symptoms such as anhedonia, amotivation, apathy and poverty of thought content, is thought to result from PFC malfunction. The neurobiology of PFC dysfunction in schizophrenia remains enigmatic, but it is now thought that, among other factors, functional hypometabolism and deficits in NMDA receptor-mediated signaling play a crucial role. It is thought that dysregulated gene expression in PFC and other brain regions of schizophrenics contributes to these defects, but the molecular pathology of transcriptional dysregulation in schizophrenia, including the underlying genetic and epigenetic mechanisms, remain unclear. In eukaryotes, including humans, changes in gene expression are typically accompanied by dynamic alterations in chromatin structure and function. Epigenetic control of gene expression, in particular, is mediated through a combinatorial set of covalent modifications at N-terminal residues of the core histones. Our central goals are 1) to find out, if in human brain, region-specific expression of NMDA receptor subunits is regulated through differential histone methylation and acetylation in chromatin surrounding 5' regulatory sequences of NMDA receptor subunit genes; and 2) to determine if, in PFC of schizophrenics, decreased expression of metabolic or NMDA receptor signaling-related mRNAs is accompanied by a deficit in open chromatin-associated histone methylation at the corresponding genes; and 3) to determine if chronic treatment with antipsychotic drugs induces epigenetic chromatin modifications at defined genomic regions in cerebral cortex. Our experiments will focus on human prefrontal and cerebellar cortex and will rely on a modified chromatin immunoprecipitation technique specifically designed for postmortem tissue. It is expected that this novel approach will provide (i) a clear picture on covalent chromatin imprints regulating gene expression in human brain and (ii) clarify if histone modifications as epigenetic regulators of gene expression contribute to transcriptional dysregulation affecting metabolism and NMDA receptor signaling in PFC of schizophrenics.

描述（由申请人提供）：前额皮质（PFC）功能障碍被认为在精神分裂症的神经生物学中发挥着关键作用。特别是，赤字综合症包括一些负面症状，例如快感缺乏、缺乏积极性、冷漠和思想内容匮乏，被认为是由前额皮质功能障碍引起的。精神分裂症中 PFC 功能障碍的神经生物学仍然是个谜，但现在认为，除其他因素外，功能性代谢低下和 NMDA 受体介导的信号传导缺陷起着至关重要的作用。人们认为精神分裂症患者前额皮质和其他大脑区域的基因表达失调是导致这些缺陷的原因之一，但精神分裂症转录失调的分子病理学，包括潜在的遗传和表观遗传机制，仍不清楚。在包括人类在内的真核生物中，基因表达的变化通常伴随着染色质结构和功能的动态变化。特别是，基因表达的表观遗传控制是通过核心组蛋白 N 端残基上的一组共价修饰组合来介导的。我们的中心目标是 1) 找出在人脑中，NMDA 受体亚基的区域特异性表达是否是通过 NMDA 受体亚基基因 5' 调控序列周围染色质中的差异组蛋白甲基化和乙酰化来调节的； 2) 确定在精神分裂症患者的 PFC 中，代谢或 NMDA 受体信号相关 mRNA 表达的减少是否伴随着相应基因的开放染色质相关组蛋白甲基化的缺陷； 3) 确定抗精神病药物的长期治疗是否会诱导大脑皮层特定基因组区域的表观遗传染色质修饰。我们的实验将重点关注人类前额叶和小脑皮质，并将依赖于专为死后组织设计的改良染色质免疫沉淀技术。预计这种新方法将提供（i）关于调节人脑基因表达的共价染色质印记的清晰图像，以及（ii）阐明组蛋白修饰作为基因表达的表观遗传调节剂是否会导致影响代谢和 NMDA 受体信号传导的转录失调。精神分裂症患者的 PFC。