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.

PUBLIC HEALTH RELEVANCE: The recent discovery that somatic cells from adult patients can be reprogrammed to a state of pluripotency enables the generation of a renewable source of disease-relevant human neurons, and the ability to study these cells under controlled conditions. Via this cellular point of entry, we are now able to design and conduct phenotypic screens of human neurons that are isogenic to psychiatric patients and use these results as a discovery tool to generate new hypotheses regarding the mechanisms underlying the most genetically intractable disorders. The overarching goal of this NCRCRG is to embark on a large-scale collaborative effort to develop a robust and reproducible platform for the iPSC-based study of psychiatric disorders, arising from a focused investigation of bipolar disorder and schizophrenia.