Alzheimer's Disease Risk Genes in Human Microglia and Neurons Derived from iPSCs

人类小胶质细胞和 iPSC 神经元中的阿尔茨海默病风险基因

基本信息

批准号：
8756320
负责人：
Li-Huei Tsai
金额：
$ 212.65万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8756320
关键词：
Accounting Alzheimer&apos s Disease Alzheimer&apos s disease risk American Astrocytes Biological Biological Assay Biomedical Research Brain Brain Part Candidate Disease Gene Cell Line Cell model Cells Characteristics Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complementary DNA Complex DNA Data Databases Disease Disease model ETS1 gene Employee Strikes Environment Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genome Human Immune Immune response Immune system Individual Inflammation Inflammatory Literature Maps Mass Spectrum Analysis Microglia Modeling Molecular Profiling Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Neurophysiology - biologic function Oligodendroglia Patients Performance Phagocytosis Pharmaceutical Preparations Phase III Clinical Trials Play Pluripotent Stem Cells Positioning Attribute Precipitation Process Proteins Proteomics RNA Reporting Resolution Risk Factors Rodent Role Subfamily lentivirinae Synapses Synaptic Transmission System Techniques Therapeutic brain cell cell type chemical release deep sequencing design disorder control functional genomics genome wide association study induced pluripotent stem cell interest knock-down mRNA Expression mouse model nerve stem cell neuroinflammation neuron loss neuroprotection novel overexpression public health relevance relating to nervous system research study risk variant small hairpin RNA tandem mass spectrometry transcription factor transcriptomics

项目摘要

DESCRIPTION (provided by applicant): The looming specter of 13.8 million Americans with Alzheimer's disease (AD) by the year 2050 motivates us to expand our biomedical research paradigm outside of the typical "cell line to rodent to human trials" model. The disappointing performance of all AD drugs that have come to Phase III clinical trials to date also forces us to think more creatively about how to study the mechanisms that underlie neurodegeneration. The advent of human induced pluripotent stem cells (iPSCs) allows us to create disease models from patients with sporadic AD as well as from those with defined familial mutations. In addition, we can use cutting-edge genome editing techniques, such as the Crispr/Cas system, to introduce disease-associated mutations into the genome of otherwise healthy human derived pluripotent cells. In the past five years, neuroscientists have made incredible advances in the creation of different brain cell types, such as neurons, astrocytes, and oligodendrocytes, from human-derived pluripotent cells. What is lacking, however, is a human cellular model of neuroinflammation, a critical component of all neurodegenerative disorders, including AD. In the current application, we describe the creation of human microglia, the brain's "immune" cell, from patient-derived and control pluripotent cells. We propose a comprehensive set of experiments that will determine the role that known and novel AD-associated genes play in these cells using cutting-edge genome editing techniques combined with high-throughput functional assays, transcriptomic profiling, and high-resolution proteomics.

描述（由申请人提供）：到 2050 年，美国将有 1380 万患有阿尔茨海默病 (AD) 的幽灵迫在眉睫，这促使我们在典型的“从细胞系到啮齿动物再到人体试验”模型之外扩展我们的生物医学研究范式。迄今为止，所有进入 III 期临床试验的 AD 药物的令人失望的表现也迫使我们更加创造性地思考如何研究神经退行性疾病的机制。人类诱导多能干细胞 (iPSC) 的出现使我们能够从散发性 AD 患者以及具有明确家族突变的患者中创建疾病模型。此外，我们可以使用尖端的基因组编辑技术，例如 Crispr/Cas 系统，将与疾病相关的突变引入健康的人源多能细胞的基因组中。在过去的五年中，神经科学家在利用人类多能细胞创建不同的脑细胞类型方面取得了令人难以置信的进展，例如神经元、星形胶质细胞和少突胶质细胞。然而，我们所缺乏的是神经炎症的人类细胞模型，神经炎症是包括 AD 在内的所有神经退行性疾病的关键组成部分。在当前的应用中，我们描述了从患者来源的多能细胞和对照多能细胞中创建人类小胶质细胞（大脑的“免疫”细胞）。我们提出了一套全面的实验，将利用尖端基因组编辑技术结合高通量功能分析、转录组分析和高分辨率蛋白质组学来确定已知和新型 AD 相关基因在这些细胞中发挥的作用。