Developing an Astroglial Model for Down Syndrome

开发唐氏综合症的星形胶质细胞模型

基本信息

批准号：
9299481
负责人：
Peng Jiang
金额：
$ 23.25万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-13 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9299481
关键词：
Adult Age Animals Astrocytes Biological Models Biological Neural Networks Brain Calcium Cell Differentiation process Cell Line Cells Chimerism Chromosomes, Human, Pair 21 Complex Development Disease Disease Progression Down Syndrome Event Functional disorder Future Generations Genetic Hippocampus (Brain)Human Human Chromosomes Immunodeficient Mouse In Vitro Individual Intellectual functioning disability Investigation Link Live Birth Long-Term Potentiation Modeling Mus Mutation Neonatal Neuraxis Neuroglia Neurons Oligodendroglia Pathogenesis Pathogenicity Patients Phenotype Play Procedures Proliferating Property Rag1 Mouse Research Personnel Rodent Role Signal Transduction Slice Stem cells Study models Synapses Synaptic Transmission System Technology Testing Therapeutic Effect Transgenic Mice Transplantation Trisomy Work base brain cell brain tissue cognitive function cognitive performance developmental disease disease phenotype drug testing fetal human tissue in vitro Model in vivo in vivo Model induced pluripotent stem cell migration mouse model nerve stem cell nervous system disorder neural circuit neuron development novel synaptic inhibition

Adult Age Animals Astrocytes Biological Models Biological Neural Networks Brain Calcium Cell Differentiation process Cell Line Cells Chimerism Chromosomes, Human, Pair 21 Complex Development Disease Disease Progression Down Syndrome Event Functional disorder Future Generations Genetic Hippocampus (Brain)Human Human Chromosomes Immunodeficient Mouse In Vitro Individual Intellectual functioning disability Investigation Link Live Birth Long-Term Potentiation Modeling Mus Mutation Neonatal Neuraxis Neuroglia Neurons Oligodendroglia Pathogenesis Pathogenicity Patients Phenotype Play Procedures Proliferating Property Rag1 Mouse Research Personnel Rodent Role Signal Transduction Slice Stem cells Study models Synapses Synaptic Transmission System Technology Testing Therapeutic Effect Transgenic Mice Transplantation Trisomy Work base brain cell brain tissue cognitive function cognitive performance developmental disease disease phenotype drug testing fetal human tissue in vitro Model in vivo in vivo Model induced pluripotent stem cell migration mouse model nerve stem cell nervous system disorder neural circuit neuron development novel synaptic inhibition

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项目摘要

Project Summary / Abstract: Title: Creating Humanized Astroglial Chimeric Mouse Brains for Modeling Down Syndrome Down syndrome (DS) arises from triplication of human chromosome 21 (HSA21) and is the most common genetic cause of intellectual disability. Our understanding on neuropathophysiology of DS is mainly gained from studies in transgenic mouse models and limited human DS fetal brain tissue. However, these strategies have limited utility because human tissues are relatively inaccessible and the mouse models only demonstrate an incomplete trisomy of HSA21. These limitations have been recently circumvented by the advent of human induced pluripotent stem cell (hiPSCs), as the iPSC technology has led to the generation of DS patient-derived hiPSCs, which presents an unprecedented opportunity for studying the pathogenesis of DS with unlimited human brain cells in vitro. While using the hiPSC-based in vitro model, basic aspects of the disease phenotypes can be examined, the consequences of these events towards the formation or disruption of neural circuits in the developing CNS can be studied only in vivo. Therefore, we propose to create a humanized chimeric mouse model with hiPSCs for studying the neuropathophysiology of DS in vivo. Specifically, the role of DS human astrocytes will be examined because astrocytes are a major cellular constituent in the central nervous system and play crucial roles in neuronal development and function. Indeed, using the astroglia and neurons differentiated from DS hiPSCs (DS astroglia and DS neurons), our in vitro study has revealed a novel and significant role of DS astroglia in causing the abnormal phenotypes of DS neurons. Recent transplantation studies demonstrated that neonatally engrafted human glial progenitor cells differentiated to astroglia and oligodendroglia in the mouse brain, which largely repopulated the adult host rodent brain, generating widespread brain chimerism. Using the established hiPSCs in our lab, here I propose to generate chimeric mouse brains that are repopulated by only human astroglia, in the absence of any human oligodendroglia or glial progenitor cells. By creating such humanized astroglial chimeric mouse brains, we seek to specifically dissect the role of astroglia in the DS pathogenesis in an in vivo system with intact neural networks. We hypothesize that engrafted diseased DS human astroglia will show abnormal signaling activity in vivo as compared to control human astroglia and this abnormal activity will further negatively regulate the synaptic activity and plasticity of the host hippocampal neural network. In this study, Aim 1 will generate chimeric mice with these well characterized DS and control human astroglia. We will optimize the transplantation procedure and characterize the differentiation, migration and distribution the human astroglia in the mouse brains at ages ranging from 3 to 6 months. Aim 2 will expand to determine the Ca2+ signaling activity of the engrafted control and DS astroglia and their effects on neuronal synaptic activity and plasticity in the hippocampus. This proposed study will create a novel hiPSC-based in vivo model for studying the effects of DS astroglia on development and formation of neural networks, and ultimately on cognitive performance of the animals. The generation of chimeric mouse with human DS astroglia will provide new opportunities for testing drugs that have therapeutic effects through targeting on astroglia. Building upon the iPSC technology, we also expect this study to serve as a template for the investigation of a variety of neurological diseases in vivo using hiPSC-derived astroglia.

项目摘要 /摘要：标题：创建人源化的星形胶质嵌合小鼠大脑，以建模唐氏综合症唐氏综合症（DS）来自人类染色体21（HSA21）的三分之一，是最多的智障的常见遗传原因。我们对DS神经病理生理学的理解主要是从转基因小鼠模型的研究和有限的人类DS胎儿脑组织中获得的。但是，这些策略的实用性有限，因为人体组织相对难以接近，仅小鼠模型证明了HSA21不完全三体。这些局限性最近已被人类诱导多能干细胞（HIPSC）的出现，因为IPSC技术导致了生成 DS患者衍生的HIPSC，它为研究DS的发病机理提供了前所未有的机会在体外无限的人脑细胞。在使用基于HIPSC的体外模型时，可以检查疾病表型，这些事件对形成或破坏的后果开发中枢神经系统中的神经回路只能在体内研究。因此，我们建议创建一个人构化嵌合小鼠模型与HIPSC一起研究体内DS的神经病理生理学。具体而言，将检查DS人星形胶质细胞的作用，因为星形胶质细胞是主要的细胞中枢神经系统的组成部分，在神经元发育和功能中起着至关重要的作用。的确，使用与DS HIPSC（DS Astroglia和DS神经元）区分开的星形胶质细胞和神经元，我们的体外研究揭示了DS星形胶质细胞在引起DS异常表型中的新颖而重要的作用神经元。最近的移植研究表明，新生儿植入了人神经胶质祖细胞与小鼠大脑中的星形胶质细胞和少突胶质细胞区分开啮齿动物的大脑，产生广泛的大脑嵌合。在我们的实验室中使用已建立的HIPSC，我在这里建议在没有任何人类的情况下，产生仅由人类星形胶质细胞重新填充的嵌合小鼠大脑少突齿或神经胶质祖细胞。通过创建这种人性化的星形胶质嵌合老鼠的大脑，我们寻求特异性地剖析了星形胶质细胞在具有完整神经的体内系统中DS发病机理中的作用网络。我们假设植入患病的DS人类星形胶质细胞会显示异常的信号传导活性与对照人的星形胶质细胞相比，体内和这种异常活性将进一步调节宿主海马神经网络的突触活动和可塑性。在这项研究中，AIM 1将产生具有这些特征良好的DS并控制人类星形胶质细胞的嵌合小鼠。我们将优化移植程序并表征人类星形胶质细胞的分化，迁移和分布老鼠的大脑年龄为3到6个月。 AIM 2将扩展以确定CA2+信号传导活动植入的控制和DS星形胶质细胞及其对神经元突触活性和可塑性的影响海马。这项拟议的研究将创建一个基于HIPSC的新型体内模型，用于研究关于神经网络发展和形成的Astroglia，最终是关于动物。人类DS Astroglia的嵌合老鼠产生将为测试提供新的机会通过靶向星形胶质体具有治疗作用的药物。在IPSC技术的基础上，我们也期望这项研究是使用体内调查多种神经疾病的模板 HIPSC衍生的星形胶质体。