Role of DISC1 and NRG1 in oligodendrocyte development in schizophrenia

DISC1 和 NRG1 在精神分裂症少突胶质细胞发育中的作用

• 批准号: 8812011
• 负责人: PAVEL Leon KATSEL
• 金额: $ 29.72万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812011
• 关键词: 1q42; Address; Adult; Affect; Animal Model; Autopsy; Axon; Brain; Brain region; Bromodeoxyuridine; Cell Cycle; Cell Cycle Arrest; Cell Differentiation process; Chromosomes; Communication; DNA; Defect; Development; Disease; Failure; Flow Cytometry; Functional disorder; Gene Expression; Gene Proteins; Genes; Genetic; Genomics; Glial Differentiation; Health; Human; IGF1 gene; Immigration; Intervention; Label; Lasers; Measures; Mediating; Mediator of activation protein; Molecular; Mus; Myelin; NRG1 gene; Nervous system structure; Neurobiology; Neuroglia; Neurons; Normal Cell; Oligodendroglia; Outcome; PDGFRA gene; Pathogenesis; Pathway interactions; Persons; Phosphorylation; Population; Predisposition; Prevention strategy; Process; Prosencephalon; Proteins; Public Health; Regulation; Research; Role; Schizophrenia; Series; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Staging; Stem cells; Superior temporal gyrus; Syndrome; Testing; Time; Transgenic Animals; Transgenic Mice; analog; area striata; cdc Genes; cell motility; hindbrain; information processing; link protein; migration; mouse model; mutant; myelination; neurotransmission; novel; oligodendrocyte precursor; precursor cell; premature; progenitor; programs; protein expression; research study; success

DESCRIPTION (provided by applicant): Schizophrenia (SZ) has been characterized as a disconnectivity syndrome where communication between different neurons, brain circuits and brain regions is disrupted leading to failures of appropriate/coherent information processing. In order to maintain functional processing and rapid neurotransmission at all levels of the nervous system, neurons require adequate myelination of their axons. The success of myelination depends on coordinated interplay of the extrinsic and intrinsic signals that mediate recruitment, differentiation and migration of oligodendrocyte precursor cells (OPC). In prior research, now replicated by many groups, we showed that SZ was characterized by significant reductions in the expression of multiple myelin and oligodendrocyte (OLG) associated genes and proteins. We also showed that the myelin related expression deficits in SZ are associated with the failure of execution of the normal cell-cycle arrest in postmitotic OLGs that may adversely affects myelin function. Genomic translocation on chromosome 1q42 associated with SZ that interrupts the disrupted-In-schizophrenia-1 gene (DISC1) may produce truncated and nonfunctional DISC1 protein. Our recent studies in transgenic mice with neuron exclusive expression of truncated human DISC1 (DhDISC1) have re- veal strong dysregulation of markers of OPC and OLGs along with cell cycle genes throughout development and adulthood suggesting that DhDISC1 can exert a major influence on proliferation and migration of oligoden drocyte precursors, their differentiation into OLGs and ultimately OLG function. The current proposal aims to gain deeper understanding into the mechanisms that contribute to the OLG dysfunction in SZ. These aims include: (1) assessing effects of neuron-exclusive DhDISC1 on migration, proliferation and differentiation of glial progenitor cells in transgenic mice and determining developmental population of glial progenitor cells targeted by DhDISC1 expression; (2) examining molecular pathways (elicited by NRG1, IGF1 and Wnt) that may mediate the effect of DhDISC1 on migration, proliferation and differentiation of OPC by studying gene/protein expression and phosphorylation of critical effectors of the pathways; (3) examining regional changes in expression of proteins connecting functionally defective DISC1 to OLG-related dysfunction in SZ in human postmortem brains and determine their disease relevance. Our approach is to understand better OLG development and function in SZ through an iterative process of identifying neurobiological abnormalities in SZ, using transgenic animal models to uncover the mechanisms responsible and validating the findings from animal models against real-world outcomes in the human brain and guide to possible preventive or interventional strategies with direct public health impact.

描述（由申请人提供）：精神分裂症（SZ）的特征是一种脱节性综合征，其中不同神经元，脑回路和大脑区域之间的通信被破坏，从而导致适当/相干信息处理的失败。为了在神经系统的各个层面上保持功能处理和快速的神经传递，神经元需要足够的轴突髓鞘形成。髓鞘化的成功取决于介导少突胶质细胞前体细胞（OPC）的外在和内在信号的协调相互作用。在现在由许多组复制的先前研究中，我们表明SZ的特征是多种髓磷脂和少突胶质细胞（OLG）相关基因和蛋白质的表达显着降低。我们还表明，SZ中的髓磷脂相关表达缺陷与有丝分裂后OLG中正常细胞周期停滞的执行失败有关，这可能会对髓磷脂功能产生不利影响。与SZ相关的1q42染色体上的基因组易位，会中断破坏的schizizophrenia-1基因（DISC1）可能会产生截短且无功能的Disc1蛋白。我们最近在转基因小鼠中使用神经元独家表达人disc1（DHDISC1）的研究具有强烈的OPC和OLGS标志物以及在整个发育和成年期间的细胞周期基因的强烈失调，这表明DHDISC1可以对少型Drocyte Prastors of olg及其不同的元素及其不同。 当前的提案旨在更深入地了解导致SZ中OLG功能障碍的机制。这些目的包括：（1）评估神经元的DHDISC1对转基因小鼠中神经胶质祖细胞的迁移，增殖和分化的影响，并确定由DHDISC1表达靶向的神经胶质祖细胞的发育群体； （2）检查分子途径（由NRG1，IGF1和WNT引起），可能通过研究基因/蛋白质表达和途径关键效应子的磷酸化来介导DHDISC1对OPC迁移，增殖和分化的影响； （3）检查在人类验尸大脑中，将功能有缺陷的盘与OLG相关功能障碍连接到功能有缺陷的盘子的蛋白质的区域变化并确定其疾病相关性。 我们的方法是通过识别SZ中神经生物学异常的迭代过程来了解SZ中更好的OLG开发和功能，使用转基因动物模型来揭示负责的机制，并验证动物模型中针对人类大脑中现实世界中的发现的发现，并指导人类的直接预防或介入策略，具有直接的公共健康影响。