Iakoucheva Lab

University of California - San Diego, Department of Psychiatry

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Research focus

The laboratory is involved in investigating molecular basis of psychiatric diseases using systems biology approaches. The goal is to discover pathways that connect genes carrying mutations identified in the exome and whole genome sequencing studies of autism and schizophrenia patients. We are building comprehensive co-expression and protein-protein interaction networks for autism and schizophrenia candidate genes and their alternatively spliced isoforms. We have built a network of interactions of over 400 brain-expressed isoforms of autism candidate genes (Nature Communications, 2014), thereby taking the autism interactome to an entirely new and more detailed level of understanding. We are also integrating brain RNA-seq data with our experimentally-derived networks to investigate how CNV and other protein-damaging mutations perturb such networks and pathways. We believe that tissue-specific networks of alternatively spliced isoforms are crucially important for improving our understanding of the mechanisms leading to psychiatric diseases. Using brain-specific spatio-temporal networks, we have identified an important pathway that is likely dysregulated by the 16p11.2 copy number changes and by autism mutations in the Cul3 ubiquitin ligase (Neuron, 2015). We found that the changes in RhoA levels might be an important factor determining microcephalic and macrocephalic phenotypes observed in the autism patients carrying these mutations. We are following up this pathway with transcriptomic and proteomic experiments in patients' fibroblast-derived and CRISPR-altered iPSC as well as the mouse model studies. Another interest of the laboratory are de novo non-coding mutations identified from the whole genome sequencing studies of autism families. We are developing computational algorithms to predict functional impact of both, coding and non-coding mutations using high-throughput genomic datasets. The long-term goal is to identify the pathways disrupted by the genetic mutations in autism and schizophrenia, and to target these pathways therapeutically.