Developing an Astroglial Model for Fragile X Syndrome

脆性X综合征（FXS）是遗传性智力残疾的最常见形式， 自闭症谱系障碍的主要遗传原因之一。我们的理解 FXS的神经病理生理学主要来自fmr1基因敲除小鼠的研究 模型然而，这些研究并不总是转化为人类的状况， 物种和可能的方式基因沉默的FXS。这些限制已经 最近被人类诱导多能干细胞（hiPSC）的出现所规避， 以及FXS患者来源的hiPSC的产生，这为 用无限的人脑细胞研究FXS的发病机制。虽然星形胶质细胞， 大脑中的非神经元细胞，在正常的大脑功能中具有广泛的作用， 越来越多地与多种脑部疾病有关，并在成年后表达FMRP， 全面了解星形胶质细胞FMRP在FXS发病机制中的作用 仍然缺乏。因此，我们将通过区分FXS和FXS， 来自对照的星形胶质细胞和FXS诱导的hiPSC。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， 提出创建具有hiPSC的人源化嵌合小鼠模型。在AIM1中，我们将 研究FXS星形胶质细胞形态、Ca2+信号传导和基因表达是如何 在体内受损。在目的2中，我们将确定FXS hIPSC-星形胶质细胞对人胶质细胞的影响。 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，并有可能发现新的 FXS的治疗目标。

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.