Developing an Astroglial Model for Fragile X Syndrome

脆性X综合征(FXS)是遗传性智能障碍的最常见形式， 自闭症谱系障碍的主要遗传原因之一。我们的理解 FXS的神经病理生理学研究主要来自于fmr1基因缺失小鼠的研究。 模特。然而，这些研究并不总是转化为人类的状况，因为 物种，可能是FXS的基因沉默方式。这些限制一直是 最近，人类诱导多能干细胞(HiPSCs)的出现绕过了这一障碍， 以及FXS患者来源的HiPSCs的产生，这为 用无限人脑细胞研究FXS的发病机制。虽然星形细胞， 大脑中的非神经细胞在正常的大脑功能中发挥着广泛的作用， 越来越多地卷入多种脑部疾病，并在成年后表达FMRP，a 全面认识星形细胞FMRP在FXS发病机制中的作用 仍然是缺乏的。因此，我们将通过分化FXS来开发人类细胞模型 对照组和FXS的星形胶质细胞可诱导出HiPSCs。为了确定FXS如何 星形胶质细胞受损以及它们如何影响神经回路的形成和功能 建议用hPSCs建立人源化嵌合小鼠模型。在Aim1中，我们将 研究FXS星形胶质细胞的形态、钙信号和基因表达 在活体内受损。在目标2中，我们将确定FXS hiPSC-星形胶质细胞对 神经元的结构和功能。这项工作有望提供重要的知识 关于人类特定星形胶质细胞在FXS中的作用，并有可能识别新的 FXS的治疗靶点。

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and one of the main identified genetic causes of autism spectrum disorder. Our understanding of neuropathophysiology of FXS is mainly gained from studies in the fmr1 null mouse model. However, these studies don’t always translate to the human condition due to species and possibly the mode of gene silencing in FXS. These limitations have been recently circumvented by the advent of human induced pluripotent stem cells (hiPSCs), and the generation of FXS patient-derived hiPSCs, which presents an opportunity for studying the pathogenesis of FXS with unlimited human brain cells. Although astrocytes, non-neuronal cells in the brain, have extensive roles in normal brain function, are increasingly implicated in multiple brain disorders and express FMRP into adulthood, a comprehensive understanding of the role of astrocytic FMRP in the pathogenesis of FXS is still lacking. We will therefore develop a human cellular model of FXS by differentiating astrocytes from control and FXS induced hiPSCs. In order to determine how FXS astrocytes are impaired and how they impact formation and function of neural circuits, we propose to create a humanized chimeric mouse model with hiPSCs. In Aim1 we will examine how FXS astrocyte morphology, Ca2+ signaling and gene expression are impaired in vivo. In Aim 2, we will determine the effect of FXS hIPSC-astrocytes on neuronal structure and function. This work is expected to provide important knowledge about the role of human specific astrocytes in FXS and has the potential to identify novel therapeutic targets for FXS.