PROJECT SUMMARY/ABSTRACT Neurodevelopmental disorders (NDDs) are characterized by disrupted development of the brain, and clinically they lead to impaired neurological function. NDDs account for ~25% of chronic pediatric disease, are incurable and result in lifelong impairments. Molecular studies have improved our understanding of NDDs, but still large gaps in knowledge exist. Conventional research tools like the mouse model does not often adequately model these conditions. Human brain organoids (hBOs) from patient-derived iPSCs can capture many characteristics and biological events in the developing brain. However, we still do not know how well human NDDs can be modeled in hBOs. Here, I propose to investigate the range of genotype-phenotype correlations observable in hBOs from a unique patient derived iPSC library of 750 independent lines to test four hypotheses: 1] NDD- derived hBOs are both sensitive and specific detectors of the underlying clinical brain pathology. 2] NDD-derived hBOs show both cellular and molecular hallmarks revealing the stages of disrupted brain development. 3] Omics approaches applied to these in-vitro derived hBOs can reveal underlying mechanisms of disrupted development. 4] Gene-environment interactions can be interrogated in hBOs. The training phase of the award, conducted in Dr. Gleeson’s lab at UCSD, outlines a comprehensive plan for acquisition of technical and professional skills that will enable my transition to an independent research position. The successful completion of this project will provide a platform for future experiments aimed to combine my expertise in stem cell fate decision to gain a deeper understanding of how does these transcriptional, epigenetic and structural specificities contribute to neurodevelopmental brain disorders.