Core C: Phenotypic screening: high throughput assay development ABSTRACT There is an urgent need to improve treatment options for patients suffering from bipolar disorder (BP) and schizophrenia (SZ). The development of patient specific iPSC based models to study the pathology and cellular and molecular bases of BP and SZ offers an unprecedented opportunity to identify improved treatments based on biology rather than symptoms, and help stratify patients according to pathological processes. While the heritability is high for BP and SZ, these disorders are genetically complex and will require the examination of multiple cell types from many patients to identify and validate phenotypes in cell-based disease models. Considering the large number of samples required to power the proposed studies, miniaturized, higher throughput assays will be essential. The function of Scientific Core C is to develop robust and reliable assays in miniaturized and higher throughput formats to support the three Research Projects. We will utilize expertise and instrumentation, including high content imaging, rapid kinetic analyses, and higher throughput electrophysiology available at the Prebys Center, a state of the art drug screening facility, which also houses a stem cell lab dedicated to establishing the technology platforms and reproducibility necessary to utilize iPSC derived cell types for phenotypic screening and drug testing. The proposed development of procedures to interrogate iPSC derived neural cell types in microtiter-well formats will be advantageous for both phenotype validation and discovery, as relatively small numbers of cells and reagents are required, making feasible testing of larger numbers of replicate samples and more variables, including timing and dose response to therapeutic agents, signaling pathway modulators, and stress inducers. In the long term, development of these assays will provide a foundation for future efforts aimed at target identification and drug discovery. Importantly, these assays will also form the bases of a standardized bank of tests against which broader panels of BP and SZ patient iPSCs, and iPSC from patients with other neuropsychiatric diseases can be screened.
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