An iPSC based humanized mouse model of dysmyelination in schizophrenia

基于 iPSC 的精神分裂症髓鞘形成障碍人源化小鼠模型

基本信息

批准号：
8927065
负责人：
STEVEN Alan GOLDMAN
金额：
$ 41.83万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927065
关键词：
Adolescent Adult Anatomy Animal Model Appearance Architecture Astrocytes Axon Biological Models Brain Cell Transplants Cells Characteristics Chimera organism Creativeness Databases Development Disease Distress Environment Etiology Evolution Fibrous Astrocyte Frequencies Functional disorder Gene Expression Gene Expression Profile Generations Genes Goals Health Hip region structure Human Image Implant Kinetics Life Mental disorders Messenger RNA Metabolic MicroRNAs Modeling Morphology Mus Myelin Neuroglia Neurons Nodal Oligodendroglia Oligonucleotides Onset of illness Pathogenesis Pathology Patients Pattern Phenocopy Phenotype Phylogenetic Analysis Physiology Population Protocols documentation Psychopathology Reagent Relative (related person)Role Schizophrenia Shivering Slice Sorting - Cell Movement Specificity Stem cells Structure Techniques Technology Time base behavioral genomics cell type density differential expression disability dysmyelination experience genetic association in vivo induced pluripotent stem cell insight mature animal migration mouse model neonatal human neuroimaging neuron loss neurophysiology novel progenitor relating to nervous system research study residence tool two-photon white matter

项目摘要

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.

描述（由申请人提供）：精神分裂症也许是人类特异性的心理病理学。它是最严重，最常见的精神疾病之一，是造成残疾，痛苦和费用的原因，但对其病因却几乎没有清楚。也就是说，精神分裂症对人类的特异性及其频繁以较少形式的与创造力，暗示其与特定人类神经能力的关联。但是，矛盾的是，基因关联研究强调了少突胶质细胞和白质基因与精神分裂症的关联，而不是人们可能期望过一种如此独特的人类病理学的神经元基因。同样，最近的影像学研究强调了精神分裂症患者中低切术的早期出现，通常很早就在疾病发作之前。这些观察结果表明，精神分裂症患者中指出的神经元组织和神经结构的异常特征可能源自神经胶质祖细胞和/或少突胶质细胞病理学，祖细胞失调，失去障碍和失败的神经元对神经元的失败，从而产生了发育中的网络结构。在此应用程序中，我们将使用一套新型技术来关注OPC和少突胶质细胞在精神分裂症的起源中的作用，通过这些技术，我们可以产生嵌合小鼠的嵌合小鼠，其神经胶质种群在很大程度上被hipsc衍生的神经胶质取代，被HIPSC衍生的神经胶质取代，其本身是源自幼体含有少年含有精神分裂症的患者。通过使用先天低霉素的颤抖小鼠作为宿主，我们可以产生白质神经胶质和髓磷脂几乎完全是人类起源的小鼠，并完全取代了人类细胞的宿主OPC和少突endroglia。为了确定该提案的可行性，我们使用精神分裂症的HIPSC OPC在髓磷脂缺陷式湿透者小鼠中建立了人神经胶质嵌合体。我们发现，最终的人神经胶质嵌合小鼠（通常在新生儿人OPC移植后均髓鞘化），而是表现出了精神分裂症患者的特征，其特征是，具有异常的OPC分散和迁移，伴随着明显的囊膜和callosalsosalsymyaseration。在此基础上，我们现在建议研究这些小鼠的白质的解剖结构和转录结构，重点是相对于正常的对照HIPSC OPC的分布，以及少突胶质细胞分化和髓磷脂形成，由精神分裂症的HIPSC OPC。然后，我们将根据mRNA和miRNA研究它们的基因表达模式，后者以定义了由精神分裂症衍生的HIPSC OPC可能经历的任何高阶转录失调。通过提供一种新的人神经胶质嵌合模型系统，以精神分裂症患者衍生的OPC形式的新细胞试剂以及新的表型特异性和与疾病相关的基因表达数据库，该项目将提供广泛而令人兴奋的新工具，功能，功能，功能和数据库。这些研究共同使我们深入了解神经胶质祖细胞的作用和它们在精神分裂症的发病机理中得出。