iPSC-based platform development for major psychiatric disorder modeling and discovery

 描述（由申请人提供）：本NCRCRG的总体目标是开发一个稳健、可扩展和可推广的平台，以使用诱导多能干细胞（iPSC）研究精神疾病的病理生理学。最近发现，成人体细胞可以重新编程为多能状态，这提出了一种令人兴奋的可能性，即人类神经元可以与患者具有相同的遗传特征，现在可以在相关细胞类型中研究疾病机制。由于这一新领域正在迅速扩大和发展，这是一个关键的时刻，汇集学术和工业合作伙伴致力于标准化iPSC生成，细胞类型特异性分化，表型测定开发，并为最终的高通量诊断和药物发现做准备。商业实体和学术机构之间的正式伙伴关系和公开交流将大大促进这一努力，确保这一过程的每一个阶段都经过验证，并符合工业过程控制和标准化。该NCRCRG由两个科学核心，一个行政核心和三个高度集成的项目组成，这些项目将在四个非营利组织和两个工业场所进行。假设驱动的项目集中在两种最常见的精神疾病，双相情感障碍（BP）和精神分裂症（SZ），使用充分表征和精心选择的BP或SZ患者队列，这些患者队列是根据锂反应性和/或遗传风险因素的存在而选择的。每个项目在至少两个患者队列中系统地评估分化方案和细胞测定。项目旨在测试和扩展我们的初步结果，这些结果显示了神经元兴奋性，线粒体功能，突触功能，钙信号传导和基因表达的稳健和部分重叠的表型。通过多个研究者在多个队列中对BP和SZ的会聚和发散细胞特征的系统研究，该组将能够测定分化方案的可靠性和再现性以及广泛验证的细胞表型。科学核心将与每个项目合作，以执行以下内容：1）验证与精神疾病相关的四种细胞类型的分化方案的一致性; 2）用于途径发现的单细胞RNA测序和转录组学，蛋白质组学和代谢组学分析;以及3）用于高通量制备，表型验证，发现和过渡到筛选平台的测定小型化。累积起来，这些实验的完成将进一步加深我们对BP和SZ之间机制相似性和差异的理解，并建立基于iPSC的精神疾病研究模型。

 DESCRIPTION (provided by applicant): The overarching goal of this NCRCRG is to develop a robust, scalable and generalizable platform to investigate the pathophysiology of psychiatric disease using induced pluripotent stem cells (iPSCs). The recent discovery that adult human somatic cells can be reprogrammed to a pluripotent state raises the exciting possibility that human neurons can be generated with the same genetic profile as patients, and disease mechanisms can now be investigated in relevant cell types. Because this new field is rapidly expanding and evolving, this is a critical time to bring together academic and industrial partners committed to standardizing the process of iPSC generation, cell type-specific differentiation, phenotypic assay development, and preparation for eventual high-throughput diagnostic and drug discovery. Formal partnerships and open communication between commercial entities and academic institutions will greatly facilitate this effort by ensuring that every stage of the proces is validated and amenable to industrial process control and standardization. This NCRCRG is composed of two scientific cores, an administrative core, and three highly integrated projects that will be performed across four nonprofit and two industrial sites. Hypothesis-driven projects are focused on two of the most common psychiatric disorders, bipolar disorder (BP) and schizophrenia (SZ), using well- characterized and carefully chosen BP or SZ patient cohorts that were selected for lithium responsiveness and/or the presence of a genetic risk factor. Each project systematically evaluates differentiation protocols and cellular assays in at least two patient cohorts. Projects are designed to test and extend our preliminary results, which show robust and partially overlapping phenotypes in neuronal excitability, mitochondrial function, synaptic function, calcium signaling, and gene expression. Through systematic investigation of convergent and divergent cellular signatures of BP and SZ in multiple cohorts, by multiple investigators, this group will be able to assay reliability and reproducibility of differentiation protocols and extensively validated cellular phenotypes. Scientific cores will work with each project to perform the following: 1) Validation of consistency of differentiation protocols for fou cell types relevant for psychiatric disease; 2) Single-cell RNA-sequencing and transcriptomic, proteomic, and metabolomic analyses for pathway discovery; and 3) Assay miniaturization for high-throughput preparation, phenotype validation, discovery, and transition to screening platforms. Cumulatively, completion of these experiments will further our understanding of the mechanistic similarities and differences between BP and SZ, and establish a model for iPSC-based investigations of psychiatric disorders.