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

 描述(由申请人提供)：NCRCRG的总体目标是开发一个强大的、可扩展的和可推广的平台，利用诱导多能干细胞(IPSCs)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，这增加了一种令人兴奋的可能性，即人类神经元可以产生与患者相同的基因图谱，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展和发展，现在是将致力于标准化IPSC生成、细胞类型特定分化、表型分析开发以及为最终高通量诊断和药物发现做准备的学术和工业合作伙伴聚集在一起的关键时刻。商业实体和学术机构之间正式伙伴关系和公开交流将极大地促进这一努力，因为它将确保这一进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。NCRG由两个科学核心、一个行政核心和三个高度整合的项目组成，这些项目将在四个非营利组织和两个工业基地执行。假设驱动的项目专注于两种最常见的精神障碍，双相情感障碍(BP)和精神分裂症(SZ)，使用特征良好和精心选择的BP或SZ患者队列，这些队列是根据锂的反应性和/或是否存在遗传风险因素而选择的。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分析。项目旨在测试和扩展我们的初步结果，这些结果显示出神经元兴奋性、线粒体功能、突触功能、钙信号和基因表达方面的强健和部分重叠的表型。通过由多名研究人员对BP和SZ在多个队列中汇聚和发散的细胞特征进行系统研究，该小组将能够测试分化方案和广泛验证的细胞表型的可靠性和重复性。科学核心将与每个项目合作，以执行以下工作：1)验证与精神疾病相关的四种细胞类型的分化协议的一致性；2)单细胞RNA测序以及转录、蛋白质组和代谢组学分析，用于通路发现；以及3)用于高通量准备、表型验证、发现和过渡到筛选平台的分析微型化。总而言之，这些实验的完成将进一步加深我们对BP和SZ在机制上的异同的理解，并建立基于IPSC的精神障碍调查模型。

 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.