Large-scale reprogramming and expression analysis of patient-derived neural cells in schizophrenia

精神分裂症患者来源的神经细胞的大规模重编程和表达分析

基本信息

批准号：
9389242
负责人：
Kristen Jennifer Brennand
金额：
$ 85.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-10 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9389242
关键词：
16p11.2 1q21 22q11.2 Adolescence Affect Age Algorithms Alpha Cell Animal Model Architecture Autopsy Bayesian Analysis Biological Assay Biology Biopsy Brain Brain Diseases Cells Child Chronic Clinical Collection Communities Complex Data Data Set Defect Development Developmental Process Diagnosis Disease Drug Targeting Ethnic Origin Etiology Fibroblasts Foundations Functional disorder Gender Gene Expression Gene Expression Profiling Gene Mutation Genes Genetic Genetic Risk Goals Heritability Heterogeneity Human Human Genetics In Vitro Incidence Individual Knowledge Laboratories Lead Lesion Libraries Literature Mental disorders Methodology Methods Modeling Molecular Molecular Profiling Mus Neurobiology Neurodevelopmental Deficit Neurons Pathogenesis Pathway Analysis Pathway interactions Patient risk Patients Persons Pharmacology Phenotype Pilot Projects Pluripotent Stem Cells Preclinical Drug Evaluation Process Risk Robotics Sample Size Sampling Schizophrenia Single Nucleotide Polymorphism Skin Somatic Cell Standardization Stem Cell Research Symptoms Testing Therapeutic Time Tissues Variant Work axon guidance base biological systems cell bank cell type cohort cost differential expression drug development drug discovery drug testing early adolescence emerging adult excitatory neuron genetic information improved induced pluripotent stem cell innovation insight migration mouse model new therapeutic target novel novel therapeutics reconstruction relating to nervous system screening tool transcriptome sequencing

项目摘要

Project summary Schizophrenia is a chronic, severe and disabling brain disorder that affects an estimated 1 in 100 persons. Though its key symptoms generally appear late in adolescence, schizophrenia is a neurodevelopmental condition with a strong genetic component and heritability estimated to be as high as 80%. Although therapeutic treatments do exist, they target few putative mechanisms and are not effective in all the patients and/or do not address all the symptoms of the disease. While there have been improvements in the understanding of the biological systems implicated in the pathogenesis and pathophysiology of schizophrenia, progress has been slow and limited both by the difficulty in obtaining relevant tissues from patients and the inadequacy of animal models to deal with the level of genetic complexity involved in this disease. To date, most of the molecular and cellular studies of schizophrenia have been performed on postmortem tissues or on genetically defined mouse models that do not fully recapitulate the human genetic risk or neural phenotype. The rapid advances in induced pluripotent stem cell (iPSC) methodology provide new opportunities to overcome some of the obstacles inherent to the modeling of neurodevelopmental diseases. As a consequence of the groundbreaking work of the Yamanaka laboratory, somatic cells from a simple patient biopsy can be reprogrammed into pluripotent stem cells that can be differentiated into other cell types, including neural cells. Because the resulting neural cells retain that individual's genetic information, this approach has tremendous potential as a tool for understanding genes and pathways that are dysregulated in schizophrenia and can provide a platform for in vitro screening assay for novel therapeutics. The first aim of the project is to apply revolutionary robotic methods to generate pluripotent stem cells from a large cohort of patients and carefully matched controls. We will then use this sample, as well as two existing samples of iPSCs with child onset schizophrenia and/ or known, rare, highly penetrant genetic lesions, to generate excitatory neurons. This will create the first large scale, highly standardized library of iPSC and neurons derived from patients with schizophrenia. The second aim of the project is to perform gene expression profiling on the schizophrenia and control neurons and use innovative systems biological analyses to identify dysregulated pathways in schizophrenia and key molecular drivers that underlie these pathway changes. These key molecular drivers represent potentially high-impact targets for drug development. Altogether, the completion of the aims will provide new insight into the neuronal pathways disrupted in schizophrenia, and identify potential drug targets. The study will also provide the community with a large schizophrenia iPSC cohort and a neuronal RNA sequencing dataset, and will lay the foundation towards establishing a high-throughput platform useful for drug screening and accelerating drug development processes.

项目概要精神分裂症是一种慢性、严重且致残的脑部疾病，估计每 100 人中就有 1 人受到影响。尽管其主要症状通常出现在青春期后期，但精神分裂症是一种神经发育疾病该病具有很强的遗传成分，遗传力估计高达80%。虽然治疗方法确实存在，但它们针对的假定机制很少，并且并非对所有患者都有效和/或没有解决疾病的所有症状。虽然在这些方面有所改进了解与精神分裂症发病机制和病理生理学有关的生物系统，进展缓慢且受到从患者获取相关组织的困难和动物模型不足以处理这种疾病所涉及的遗传复杂性水平。迄今为止，大多数精神分裂症的分子和细胞研究都是在死后组织或尸体上进行的。基因定义的小鼠模型不能完全概括人类遗传风险或神经表型。诱导多能干细胞 (iPSC) 方法学的快速进展为克服神经发育疾病建模固有的一些障碍。结果山中实验室的开创性工作是，从简单的患者活检中提取的体细胞可以重新编程为多能干细胞，可以分化为其他细胞类型，包括神经细胞。由于产生的神经细胞保留了个体的遗传信息，因此这种方法具有巨大的意义作为了解精神分裂症失调基因和通路的工具的潜力为新疗法的体外筛选试验提供平台。该项目的首要目标是应用革命性的机器人方法从大量患者中仔细生成多能干细胞匹配的控件。然后，我们将使用该样本以及两个现有的儿童发病 iPSC 样本精神分裂症和/或已知的、罕见的、高度渗透性的遗传病变，以产生兴奋性神经元。这将创建第一个大规模、高度标准化的 iPSC 和源自患有以下疾病的患者的神经元库精神分裂症。该项目的第二个目标是对精神分裂症和精神分裂症进行基因表达谱分析。控制神经元并使用创新系统生物分析来识别失调的通路精神分裂症和这些途径变化背后的关键分子驱动因素。这些关键分子驱动因素代表药物开发的潜在高影响目标。总而言之，目标的完成将提供对精神分裂症中受损的神经元通路的新见解，并确定潜在的药物靶点。该研究还将为社区提供大型精神分裂症 iPSC 队列和神经元 RNA 测序数据集，将为建立可用于药物的高通量平台奠定基础筛选和加速药物开发过程。