Developing an Astroglial Model for Fragile X Syndrome

开发脆性 X 综合征的星形胶质细胞模型

基本信息

批准号：
10317618
负责人：
Anna Dunaevsky
金额：
$ 43.44万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317618
关键词：
Address Adult Affect Astrocytes Brain Brain Diseases Cell Line Cell Nucleus Cell model Chimera organism Clinical Trials Complex Dendritic Spines Development Disease Exhibits FMR1 Fragile X Syndrome Gene Expression Gene Silencing Generations Genetic Goals Human Image Impairment Inherited Intellectual functioning disability Knockout Mice Knowledge Modeling Molecular Morphology Mus Mutation Neuroglia Neurons Neuropathogenesis Neurophysiology - biologic function Pathogenesis Pathology Patients Primates Property Public Health Research Proposals Role Sensory Signal Transduction Structure Study models Testing Translating Work astrocyte progenitor autism spectrum disorder base behavioral impairment brain cell functional disability human model in vivo induced pluripotent stem cell mouse model neural circuit neuron development neuronal excitability new therapeutic target novel stem cell biology transcriptome sequencing

项目摘要

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.

脆弱的X综合征（FXS）是遗传性智障的最常见形式，自闭症谱系障碍的主要确定遗传原因之一。我们的理解 FXS的神经病理生理学主要是从FMR1 Null小鼠的研究中获得的模型。但是，这些研究并不总是转化为由于物种和可能的基因沉默模式。这些限制已经最近，人类诱导多能干细胞（HIPSC）的冒险经历了以及FXS患者衍生的HIPSC的产生，这是一个机会研究无限型人脑细胞FXS的发病机理。虽然星形胶质细胞，大脑中的非神经元细胞在正常大脑功能中具有广泛的作用，为越来越涉及多种脑部疾病，并将FMRP表达为成年，一个全面了解星形胶质细胞FMRP在FXS发病机理中的作用仍然缺乏。因此，我们将通过区分FXS的人类细胞模型来自对照和FXS诱导HIPSC的星形胶质细胞。为了确定FXS 星形胶质细胞受到影响以及它们如何影响神经回路的形成和功能，我们提出使用HIPSC创建人源化嵌合小鼠模型的建议。在AIM1中，我们将检查FXS星形胶质细胞形态，CA2+信号传导和基因表达如何体内受损。在AIM 2中，我们将确定FXS HIPSC-ASSTROCYTES对神经元结构和功能。期望这项工作提供重要的知识关于人类特异性星形胶质细胞在FXS中的作用，并具有识别新颖的潜力 FXS的治疗靶标。