S183. ABNORMALITIES IN SERINE/THREONINE SIGNALING NETWORKS IN SEVERE NEUROPSYCHIATRIC ILLNESS: DEVELOPMENT OF A PIPELINE TO EXPLORE ABNORMALITIES OF KINASE ACTIVITY AND IDENTIFY NOVEL TREATMENT STRATEGIES FOR SCHIZOPHREN

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Abstract Background Abnormalities of cellular signaling are well characterized in neuropsychiatric illnesses, including schizophrenia. Changes in signaling pathways reflect the underlying genetic, environmental, and epigenetic perturbations driving disease phenotypes. A shortcoming of most signaling studies is a focus on one or a few protein kinases at a time, a limitation since protein kinases work in networks with other kinases, phosphatases, and regulatory molecules to effect signaling events. We addressed this challenge by employing a kinome array platform that simultaneously measures protein kinase activity at hundreds of reporter peptide substrates. We then developed a novel bioinformatics pipeline to identify protein kinase nodes, signaling networks, upstream biological pathways, and drug candidates that “reverse” kinomic disease signatures. Methods Postmortem DLPFC brain samples from subjects with schizophrenia (n = 20 per group, 10 males and 10 females per group), were compared to age, PMI and pH matched control subjects (n = 20 per group, 10 males and 10 females per group) using the Pamgene12 serine/threonine kinome array chip. Samples were pooled by diagnosis and gender, and run in triplicate. The R-shiny app KRSA was created to automate assignment of kinases, perform permutation analyses, identify biological pathways, and connect to iLINCs for identification of drug

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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