权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

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.

项目概要/摘要：标题：创建人源化星形胶质细胞嵌合小鼠大脑用于唐氏综合征建模唐氏综合征（DS）是由人类21号染色体（HSA 21）的三倍体引起的，智力残疾的常见遗传原因。我们对DS的神经病理生理学的理解主要是从转基因小鼠模型和有限的人类DS胎儿脑组织的研究中获得。但这些这些策略的效用有限，因为人体组织相对难以接近，证明HSA 21的不完全三体。最近，这些限制已被人类诱导多能干细胞（hiPSC）的出现，因为iPSC技术已经导致了 DS患者来源的hiPSCs，这为研究DS的发病机制提供了前所未有的机会无限的人脑细胞。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发育中的中枢神经系统的神经回路的研究只能在体内进行。因此，我们建议设立一个具有hiPSC的人源化嵌合小鼠模型用于研究DS的体内神经病理生理学。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一种主要的细胞，它是中枢神经系统的重要组成部分，在神经元的发育和功能中起着关键作用。的确，使用从DS hiPSC分化的星形胶质细胞和神经元（DS星形胶质细胞和DS神经元），我们在体外一项新的研究揭示了DS星形胶质细胞在导致DS异常表型中的重要作用神经元最近的移植研究表明，新生儿移植的人类胶质祖细胞在小鼠脑中分化为星形胶质细胞和少突胶质细胞，这些细胞在很大程度上重新填充了成年宿主啮齿动物的大脑，产生广泛的大脑嵌合体。使用我们实验室中已建立的hiPSC，在这里我建议在没有任何人类神经胶质细胞的情况下，少突胶质细胞或胶质祖细胞。通过创造这种人源化的星形胶质细胞嵌合小鼠大脑，我们寻求为了在具有完整神经元的体内系统中具体剖析星形胶质细胞在DS发病机制中的作用，网络.我们假设移植的患病DS人星形胶质细胞在细胞内会表现出异常的信号活性，与对照人星形胶质细胞相比，这种异常活性将进一步负调节人星形胶质细胞的增殖。宿主海马神经网络的突触活性和可塑性。在这项研究中，目标1将产生具有这些充分表征的DS的嵌合小鼠和对照人类星形胶质细胞。将优化本研究旨在探讨人星形胶质细胞在移植过程中的分化、迁移和分布在3到6个月大的小鼠大脑中。目的2将扩展以确定Ca 2+信号传导活性移植的对照和DS星形胶质细胞及其对神经元突触活性和可塑性的影响，海马体。这项拟议的研究将建立一种新的基于hiPSC的体内模型，用于研究 DS星形胶质细胞对神经网络的发育和形成，并最终对认知性能的影响动物人DS星形胶质细胞嵌合体小鼠的产生将为实验研究提供新的机会通过靶向星形胶质细胞发挥治疗作用的药物。基于iPSC技术，我们还我希望这项研究可以作为一个模板，用于研究各种神经系统疾病在体内使用 hiPSC衍生的星形胶质细胞。