An iPSC based humanized mouse model of dysmyelination in schizophrenia

描述（由申请人提供）：精神分裂症可能是最具人类特异性的精神病理学。它是最严重和最常见的精神疾病之一，是造成巨大残疾、痛苦和费用的原因，但其病因仍不清楚。也就是说，精神分裂症对人类的特异性，以及它在较小形式中与精神分裂症的频繁联系， 创造力，这表明它与特定的人类神经能力有关。但奇怪的是，基因关联研究强调了少突胶质细胞和白色物质基因与精神分裂症的关联，而不是人们可能认为的人类特有的病理学的神经元基因。同样，最近的放射学研究强调了精神分裂症患者髓鞘形成不足的早期表现，通常早在疾病发作之前。这些观察结果表明，精神分裂症患者中神经元组织和神经炎结构的异常特征可能来自神经胶质祖细胞和/或少突胶质细胞病理学，祖细胞失调，髓鞘形成障碍和神经元的少突胶质细胞支持失败，产生发育中断的网络结构。在本申请中，我们将重点关注OPC和少突胶质细胞在精神分裂症发生中的作用，使用一套新的技术，通过该技术，我们可以产生嵌合小鼠，其胶质细胞群已在很大程度上被hiPSC衍生的胶质细胞所取代，这些胶质细胞本身来自青少年发作的精神分裂症患者。通过使用先天性低髓鞘震颤小鼠作为宿主，我们可以产生其白色胶质细胞和髓鞘几乎完全来自人类的小鼠，宿主OPCs和少突胶质细胞完全被人类细胞取代。 为了确定该提议的可行性，我们使用精神分裂症衍生的hiPSC OPC在髓鞘缺陷的颤抖小鼠中建立了人神经胶质嵌合体。我们发现，由此产生的人神经胶质嵌合小鼠-通常在新生儿人OPC移植后髓鞘形成良好-相反，表现为精神分裂症患者特有的髓鞘形成不足，异常OPC分散和迁移伴随明显的囊和胼胝体髓鞘形成障碍。在此基础上，我们现在提出研究这些小鼠的白色物质的解剖学和转录结构，重点是它们的移植OPCs相对于正常对照hiPSC OPCs的分布，以及精神分裂症衍生的hiPSC OPCs的少突胶质细胞分化和髓鞘形成。然后，我们将研究它们的基因表达模式，在mRNA和miRNA方面，后者以便定义精神分裂症衍生的hiPSC OPC可能经历的任何高阶转录失调。通过提供一个新的人类神经胶质嵌合模型系统，新的细胞试剂形式的精神分裂症患者衍生的OPC，和新的表型特异性和疾病相关的基因表达数据库，该项目将提供一个广泛的和令人兴奋的新的工具，能力和数据库。总之，这些研究应该为我们提供了很好的了解神经胶质祖细胞的作用， 精神分裂症的发病机制中的衍生髓鞘。

DESCRIPTION (provided by applicant): Schizophrenia is perhaps the most human-specific psychopathology. It is one of the most severe - and common - psychiatric disorders, a cause of tremendous disability, distress and expense, and yet little remains clear about its etiology. That said, the specificity of schizophrenia to humans, and its frequent association in lesser forms with creativity, suggest its association with specifically human neural competencies. Paradoxically though, gene association studies have highlighted the association of oligodendrocytic and white matter genes with schizophrenia, rather than the neuronal genes that one might have expected of a pathology so uniquely human. Similarly, recent radiographic studies have highlighted the early appearance of hypomyelination in schizophrenics, often long before disease onset. These observations suggest that the aberrant features of neuronal organization and neuritic structure noted in schizophrenics might derive from glial progenitor and/or oligodendrocytic pathology, with progenitor dysregulation, dysmyelination and failed oligodendrocytic support of neurons yielding a developmentally-disrupted network structure. In this application, we will focus on the roles of OPCs and oligodendroglia in the genesis of schizophrenia, using a novel set of technologies by which we can produce chimeric mice whose glial populations have been largely replaced by hiPSC-derived glia, themselves derived from patients with juvenile-onset schizophrenia. By using congenitally hypomyelinated shiverer mice as hosts, we can generate mice whose white matter glia and myelin are almost entirely of human origin, with complete replacement of host OPCs and oligodendroglia by human cells. To establish the feasibility of this proposal, we established human glial chimeras in myelin-deficient shiverer mice, using schizophrenia-derived hiPSC OPCs. We found that the resultant human glial chimeric mice - which typically myelinate well following neonatal human OPC transplants - instead phenocopied the hypomyelination so characteristic of schizophrenic patients, with aberrant OPC dispersal and migration accompanying overt capsular and callosal dysmyelination. On that basis, we now propose to study the anatomy and transcriptional architecture of the white matter of these mice, focusing on the distribution of their engrafted OPCs relative to normal control hiPSC OPCs, as well as on oligodendrocytic differentiation and myelin formation by schizophrenia-derived hiPSC OPCs. We will then investigate their gene expression patterns, in terms of both mRNA and miRNA, the latter so as to define any higher-order transcriptional dysregulation that may be experienced by the schizophrenia-derived hiPSC OPCs. By providing a new human glial chimeric model system, new cellular reagents in the form of schizophrenic patient-derived OPCs, and new phenotype-specific and disease-associated gene expression databases, this project will make available a broad and exciting new set of tools, capabilities and databases. Together, these studies should provide us great insight into the role of glial progenitor cells and their derived myelin in the pathogenesis of schizophrenia.