The main research of this laboratory revolves around the molecular basis of neuronal aging. We study how excess reactive oxygen species (ROS) modify K+ channels and how this process contributes to the progressive decline of neuronal function, which is part of normal aging as well as neurodegenerative disease. The journey into what at the time was uncharted territory began when we decided to test the idea that the ROS that build up in cells during aging may oxidize K+ channels causing neuronal failure. For that exploratory inquiry we took advantage of the simplicity and powerful genetics of Caenorhabditis elegans which indeed turned out to be an excellent tool to capture the essence of the problem. In short, we demonstrated that oxidation of a K+ channel named KVS-1 during aging causes sensorial decline in the worm. Encouraged by those results, we pursued our inquiry into vertebrates and found that KCNB1 (Kv2.1), a voltage-gated K+ channel abundant in the brain and homolog to KVS-1, is susceptible to redox.
We now know that oxidation of KCNB1 channels constitutes a pervasive mechanism of neurotoxicity. Oxidized KCNB1 channels are present in the post mortem human hippocampi of control aging donors and in significantly larger amounts in the hippocampi of Alzheimer's disease (AD) donors. Furthermore, KCNB1 oxidation increases neuronal loss and impairs cognitive function in mouse models of AD (3xTg-AD background) and traumatic brain injury (TBI). These two conditions are associated with multiple etiologies and pathogenic mechanisms but share robust oxidative stress and plaque formation. Moreover, in both AD and TBI mouse models, the toxic effects associated with oxidation of the KCNB1 channel are moderated by Dasatinib, a FDA-approved anti-cancer drug.
Current projects focus on elucidating the molecular basis for the neurotoxic effects of KCNB1 oxidation, to identify and characterize common neurotoxic pathways in the AD and the TBI brains and to clinically test the potential therapeutic of Dasatinib for the treatment of Alzheimer's disease. We employ genetics, behavioral analysis, biochemistry, histochemistry and electrophysiology techniques.
A second line of research, seeks to transform patented technology developed in the lab into a commercial reality. This effort uses C. elegans as a proxy to identify potentially efficacious drugs during the early stages of the screening process. Currently, we are working in collaboration with a major pharmaceutical company to validate our technology to industry standards.
The research of the laboratory is funded by the National Institutes of Health and by the National Science Foundation.