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）：前额叶皮层（PFC）的功能障碍被认为在精神分裂症的神经生物学中起关键作用。特别是，赤字综合征包括诸如Anhedonia，动机，冷漠和思想含量贫困等负面症状的子集，被认为是由PFC故障引起的。精神分裂症中PFC功能障碍的神经生物学仍然是神秘的，但现在认为，NMDA受体介导的信号传导的功能低代谢和缺陷起着至关重要的作用。据认为，PFC和精神分裂症患者其他大脑区域的基因表达失调会导致这些缺陷，但是精神分裂症中转录失调的分子病理学（包括基本的遗传和表观遗传机制）仍然不清楚。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。尤其是基因表达的表观遗传控制是通过核心组蛋白的N末端残基的共价修饰组组合来介导的。我们的中心目标是1）找出，如果在人脑中，NMDA受体亚基的区域特异性表达通过围绕NMDA受体亚基基因的5'调节序列的染色质差异组蛋白甲基化和乙酰化来调节； 2）为了确定在精神分裂症患者的PFC中，代谢或NMDA受体信号相关的mRNA的表达是否降低，伴随着相应基因的开放染色质相关组蛋白甲基化的不足； 3）确定用抗精神病药的慢性治疗是否在大脑皮层中定义的基因组区域诱导表观遗传染色质修饰。我们的实验将集中在人类的前额叶和小脑皮层上，并将依赖于专门为验尸组织设计的改良染色质免疫沉淀技术。可以预期，这种新颖的方法将提供（i）关于共价染色质的清晰图片，可以调节人脑中的基因表达，并且（ii）阐明基因表达的表观遗传调节剂是否有助于转录失调，从而导致影响代谢性和NMDA受体信号的转录失调。