Newly emerged, rapid acting antidepressant ketamine is able to achieve therapeutic improvement, in part, through stimulating activity of kinase-dependent signaling pathways. However, current investigations are limited to a single or small number of kinases and are unable to detect novel kinases. The goal of the proposed project is to uncover mechanisms underlying ketamine's antidepressant actions through a unique unbiased high-throughput screening. We propose to use a chemical proteomics approach that couples multiplexed inhibitor beads (MIBs) technology with quantitative mass spectrometry (MS) to capture kinases and their substrates that are activated by ketamine and its active metabolite HNK. This approach will open up a new realm of opportunities to link ketamine treatment with its underlying molecular mechanisms at the proteomics level. Kinases and pathways identified through the profiling approach will be subject for verification and in-depth examination. Preliminary application of this MIBs/MS approach replicated well-known molecular signature of ketamine action identified previously, including mTOR and ERK pathways. Furthermore, preliminary results suggest unchecked kinase activity and unappreciated pathways that mediate initial neural responses to ketamine as well as synaptogenesis induced by ketamine as a means of functional restoration. We expect our effort in identifying novel mechanisms underlying ketamine antidepressant actions to provide unmet therapeutic opportunities in treating depression and possibly other mood disorders.
Depression is one of the most prevalent and debilitating mental illnesses. Patients with major depressive disorder (MDD) suffer from lack of rapid, safe, and efficacious treatment. Recent clinical studies demonstrate that ketamine at sub-anesthetic dosage produces rapid and long-lasting antidepressant responses in MDD patients. Research is proposed to identify physiological and molecular mechanisms underlying the antidepressant effects of ketamine that might yield promising new drug targets for treating depression and possibly other mood disorders. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help reduce the burdens of human disability through improvement of mental health aspects.
