Imaging transcriptomics across developmental stages of early psychotic illness

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PROJECT SUMMARY/ABSTRACT As a physician-scientist in neurodevelopmental research with a strong background in molecular neuroscience, I seek mentored support for training in novel analytics to integrate neuroimaging and molecular genetics data in humans, on my path toward becoming an independent investigator. I propose an integrative project focusing on a prospective longitudinal cohort of youth at clinical high risk (CHR) for psychosis (NAPLS2) that utilizes advances in neuroimaging analyses and high throughput, publicly available brain-wide transcriptomic atlases to investigate neurodevelopmental mechanisms of schizophrenia (SZ) risk. Prior work suggests that cognitive dysfunction is a core feature of SZ, with working memory (WM) typically maturing throughout adolescence when overt clinical psychosis onset is most common, and WM depends, in part, on widely distributed cortical glutamate- and GABA-mediated neural circuitry. However, prevention and treatment of cognitive dysfunction in SZ is limited. This project incorporates cross-sectional and longitudinal in vivo neuroimaging data from the NAPLS2 cohort with publicly available human postmortem brain transcriptome data to test whether morphometric similarity networks and cognitive impairments are differentially affected in CHR youth that develop psychosis, whether these cortical patterns are linked to behavioral measures of WM, and whether affected frontotemporal regions have a unique pattern of glutamate/GABA transcript enrichment affected by SZ risk genes. If these hypotheses are confirmed, the project will provide evidence that cortical alterations are detectable prior to overt illness onset and associated with behavioral and molecular measures of cognitive dysfunction. To attain these research aims, I seek formal training in imaging genomics and longitudinal analysis methods, which is possible through structured coursework, mentoring from a team of distinguished scientists, and UCLA’s outstanding infrastructure for genomics, neuroimaging, and psychosis research. The primary mentor (Dr. Bearden) has internationally recognized expertise in psychosis and prospective longitudinal studies of related neurocognitive and neuroimaging phenotypes, with extensive experience as a successful research mentor. The core co-mentors have complementary expertise in bioinformatics and functional genomics (Dr. Gandal) and statistical genetics methods (Dr. Pasaniuc) critical for this proposal. My collaborator (Dr. Raznahan) has renowned expertise in developmental neuroimaging. A key consultant (Dr. Freimer) will allow for shared bioinformatics resources and core facilities to guide analyses in large-scale functional and developmental genomics approaches, and will provide focused training in lab leadership and career development. This K proposal will provide me with the in-depth training in research methodology and career support necessary for a successful transition to independence. This proposal aligns with the NIMH strategic objectives to define brain mechanisms underlying complex behaviors and to study mental illness trajectories across the lifespan.