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

• 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
• 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

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.

项目总结 精神分裂症是一种慢性、严重和致残的大脑疾病，估计每100人中就有1人受到影响。 虽然精神分裂症的主要症状通常出现在青春期较晚，但它是一种神经发育 具有很强的遗传成分和遗传力估计高达80%的疾病。虽然 治疗方法确实存在，它们针对的可能机制很少，而且并不是对所有患者都有效。 和/或没有解决疾病的所有症状。虽然在以下方面有所改进 了解与精神分裂症的发病机制和病理生理学有关的生物系统， 进展缓慢且受限，既有从患者那里获取相关组织的困难，也有 动物模型不足以处理这种疾病所涉及的遗传复杂性水平。到目前为止， 大多数关于精神分裂症的分子和细胞研究都是在死后组织或在 不能完全概括人类遗传风险或神经表型的基因定义的小鼠模型。 诱导多能干细胞(IPSC)方法学的快速发展为 克服神经发育疾病建模所固有的一些障碍。结果就是 在山中实验室的开创性工作中，来自简单患者活检的体细胞可以 重新编程为多能干细胞，可以分化为其他类型的细胞，包括神经细胞。 因为由此产生的神经细胞保留了个体的遗传信息，这种方法具有巨大的 有可能作为一种工具来理解精神分裂症中调节失调的基因和通路 为新药的体外筛选试验提供平台。该项目的第一个目标是应用 革命性的机器人方法，从一大群患者中小心地产生多能干细胞 配对的对照组。然后，我们将使用此样本，以及两个现有的儿童发病的IPSCs样本 精神分裂症和/或已知的、罕见的、高度渗透性的遗传损伤，以产生兴奋性神经元。这将是 创建第一个大规模、高度标准化的IPSC和来自患者的神经元库 精神分裂症。该项目的第二个目标是对精神分裂症和 控制神经元并使用创新的系统生物学分析来识别失控的通路 精神分裂症和这些途径变化背后的关键分子驱动因素。这些关键的分子驱动因素 代表了药物开发的潜在高影响目标。总之，这些目标的完成将 为精神分裂症中被破坏的神经元通路提供新的见解，并确定潜在的药物靶点。 这项研究还将为社区提供一个大型精神分裂症IPSC队列和神经元RNA 测序数据集，将为建立用于药物的高通量平台奠定基础 筛选和加快药物开发进程。