Most experimental approaches to elucidating complex therapeutic drug function are not evolutionarily informed, i.e., they use model organism merely as human surrogates. In contrast, my strategy is to use model organisms to assemble conceptual building blocks. My evolutionary pharmacology approach to understanding complex therapeutic drug function starts from the counterintuitive assumption that ancient cellular processes, which emerged in our early eukaryotic ancestors, are not merely inert relicts preserved in humans, but actually are fundamental components of disease processes that have previously seemed uniquely human. I will deploy rapidly advancing DNA sequencing technologies, alongside the tools of chemical biology and high-resolution imaging analysis, to accelerate hypothesis generation and ortholog discovery in the powerful model eukaryote Saccharomyces cerevisiae a.k.a. baker’s or brewer’s yeast. I intend to pursue my current initial focus on psychiatric-disease drugs, but also to broaden the scope over time.
Specific Project Areas
Dissecting the membrane-based pharmacology of the SSRI antidepressant sertraline (Zoloft®)
The neurotrophic hypothesis of antidepressant function states that synaptic monoamine (e.g., serotonin) reuptake is necessary but not sufficient to explain the breadth of cell physiological effects of antidepressants, in particular the time lag associated with the onset of therapeutic effectiveness in humans. Our work on sertraline accumulation in cellular membranes of yeast has led to a preliminary model that provides for the first time a testable molecular framework for the neurotrophic hypothesis, which we are investigating in the rat neuronal cell line PC12.
Systematic identification of conserved pathways targeted by psychiatric-disease drugs
Elucidation of the phenotypic effects of psychiatric-disease drugs in humans present unique challenges, because these compounds have complex pharmacology, i.e., multiple molecular targets, including proteins and lipids. We are making plans to generalize a yeast-centered forward genetics approach beyond tricyclics and SSRIs to other psychopharmacological classes bedeviled by molecular promiscuity: antipsychotics (both typical and atypical), and antihistamines (both sedating and non-sedating).
Evolutionarily informed models of synapse evolution
The virtues of an evolutionary neuropharmacology approach are that it can be applied to questions rooted in basic neuroscience. I therefore propose a yeast-centered study of the maintenance of cell membrane homeostasis during vesicular transport as a simplified model of the functional neuronal synapse, specifically the synaptic vesicle life cycle. We are developing a quantitative model of the coordination between clathrin dynamics and vacuolar ATPase complex activity in the fungal secretory pathway, as these two pathways were identified in our original selection for sertraline overdose resistance, and they play vital roles in synaptic homeostasis, and synaptogenesis.