The Role of ApoE in Neuroplasticity and A-beta; Clearance using iPS Cell-Derived Astrocytes

ApoE 在神经可塑性和 A-β 中的作用；

基本信息

批准号：
8849264
负责人：
Wayne W Poon
金额：
$ 18.54万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8849264
关键词：
Address Affect Age Alleles Alzheimer&apos s Disease Amyloid Apolipoprotein E Astrocytes Biology California Cell Line Cells Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Collaborations Confocal Microscopy Dementia Dendritic Spines Disease Environmental Risk Factor Exposure to Flow Cytometry Gene Expression Genes Genetic Genetic Polymorphism Genotype Glutamate Metabolism Pathway Growth Human Immunoassay Incubated LDL-Receptor Related Protein 1 Label Link Masks Mediating Microfluidics Modeling Molecular Morphology Mus Neurofibrillary Tangles Neuronal Plasticity Neurons Other Genetics Pathogenesis Pathology Patients Phagocytosis Population Protein Isoforms Research Risk Risk Factors Role Synapses Testing Transplantation Universities Xenograft procedure abstracting age related amyloid pathology apolipoprotein E-3 apolipoprotein E-4 base fetal genetic risk factor genome editing improved in vivo induced pluripotent stem cell innovation monomer mouse model neuropathology neurotoxic novel research study synaptogenesis tau Proteins tau aggregation transmission process

项目摘要

Project 3: The Role of ApoE in Neuroplasticity and A¿ Clearance using iPS Cell-Derived Astrocytes Project Summary/Abstract This proposal aims to utilize patient iPS cell-derived astrocytes to investigate the role of apolipoprotein E (apoE) on AD risk at the molecular level. While mouse models have greatly improved our understanding of AD pathogenesis, the molecular and cellular mechanisms by which apoE influences human neuronal function and degeneration remain largely unknown. ADRC patient-derived astrocyte will be used to determine how APOE genotype affects astrocyte function and using a novel human astrocyte/neuronal co-culture, determine the role of apoE isoforms on synapse formation/plasticity and to investigate how synaptic vulnerability to A¿ and tau is influenced. Recent studies suggest that apoE may also influence astrocyte-mediated A¿ clearance. We will therefore determine whether the different apoE isoforms alter the rate of A¿ phagocytosis by human astrocytes and influence the neuron-neuron transmission of tau. The proposed studies will utilize 12 lines of patient- derived iPS cells provided by the ADRC iPS Cell Core (6-APOE ¿3/¿3 and 6-APOE ¿4/¿4). In collaboration with the iPS Cell Core, we will also use CRISPR-mediated genome editing to convert an APOE ¿4/¿4 iPS cell line into an isogenic APOE ¿3/¿3 line to allow us to compare genetically homogenous human astrocytes that differs only by the APOE allele. Lastly, iPS cell-derived astrocytes will be transplanted into xenotransplantation- compatible Rag-5xfAD and Rag-tau mice to examine the effects of apoE on amyloid and tau pathology in vivo.

项目3：使用IPS细胞衍生的星形胶质细胞，APOE在神经塑性和A的清除中的作用项目摘要/摘要该建议旨在利用患者IPS细胞衍生的星形胶质细胞来研究载脂蛋白E的作用（APOE）在分子水平上的AD风险。鼠标模型极大地改善了我们对广告的理解发病机理，APOE影响人类神经元功能的分子和细胞机制堕落仍然很大未知。 ADRC患者衍生的星形胶质细胞将用于确定APOE 基因型影响星形胶质细胞功能并使用新型的人类星形细胞/神经元共培养，确定该作用突触形成/可塑性上的Apoe同工型的属性，并研究突触的脆弱性和tau是如何受影响。最近的研究表明，APOE也可能影响星形胶质细胞介导的清除。我们将因此，确定不同的APOE同工型是否改变了人类星形胶质细胞的吞噬作用率并影响tau的神经神经元传播。拟议的研究将利用12条患者 - 由ADRC IPS细胞核提供的衍生IPS细胞（6-apoe€3/€3和6-apoe€4/€4）。与 IPS细胞核心，我们还将使用CRISPR介导的基因组编辑来转换APOE„ 4/€4 IPS细胞系进入等源性apoe€3/€3线，使我们能够比较一般均匀的人类星形胶质细胞，从而有所不同仅由Apoe等位基因。最后，IPS细胞衍生的星形胶质细胞将被移植到异种移植中兼容的RAG-5XFAD和RAG-TAU小鼠，以检查ApoE对体内淀粉样蛋白和Tau病理学的影响。