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

• 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
• 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' s Disease; Alzheimer' 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

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，1380万美国阿尔茨海默病(AD)患者的幽灵迫在眉睫，这促使我们将生物医学研究范式扩展到典型的“从细胞到啮齿动物再到人体试验”的模式之外。到目前为止，所有进入第三阶段临床试验的AD药物的表现都令人失望，这也迫使我们更具创造性地思考如何研究神经变性的机制。人类诱导多能干细胞(IPSCs)的出现使我们能够从散发性AD患者和具有明确家族突变的患者中创建疾病模型。此外，我们可以使用尖端基因组编辑技术，如Crispr/Cas系统，将与疾病相关的突变引入到原本健康的人类来源的多能细胞的基因组中。在过去的五年里，神经科学家在从人类来源的多能细胞创造不同类型的脑细胞方面取得了令人难以置信的进展，如神经元、星形胶质细胞和少突胶质细胞。然而，缺乏的是神经炎症的人类细胞模型，这是包括AD在内的所有神经退行性疾病的关键组成部分。在目前的应用中，我们描述了从患者来源的和对照的多能细胞中创造出人类小胶质细胞，即大脑的“免疫”细胞。我们提出了一套全面的实验，利用尖端基因组编辑技术结合高通量功能分析、转录图谱和高分辨率蛋白质组学来确定已知和新的AD相关基因在这些细胞中所起的作用。