I am currently a Research Assistant Professor within the Conn group. I obtained my Ph.D. in 1996 in the lab of Dr. Ronald Emeson at Vanderbilt. During my graduate career I studied the regulation of RNA editing in the mammalian central nervous system and characterized molecular determinants regulating RNA editing events within the AMPA subtype glutamate receptor, GluR2, and the G protein-coupled 5HT 2C serotonin receptor. I then pursued postdoctoral studies with Dr. Stan McKnight at the University of Washington, focusing on the study of Protein Kinase A signal transduction using recombinant mouse lines and genetically engineering mutations within the PKA enzyme.

I joined the Conn lab in 2004 and have focused on the development of high throughput-compatible assays to search for ligands specific for G protein-coupled receptors (GPCRs) of the muscarinic and metabotropic glutamate receptor families. We have now developed a new assay which measures Gi/o-coupled GPCR regulation of the inwardly rectifying potassium channel, GIRK. This assay exploits the ability of potassium channels to conduct the ion thallium; after loading cells with the fluorescent dye BTC-AM, GPCR agonist-induced thallium influx causes an increase in fluorescence that is amenable to measurement in HTS format. We have now used this strategy to sensitively detect the activity of agonists, antagonists, and allosteric modulators of Gi/o-coupled GPCRs in a direct, time-efficient, and cost-effective manner, expanding the repertoire of assays that can be used for the discovery of new pharmacological tools and lead therapeutics for this important class of signaling molecules .

During my time in the Conn lab, I have become particularly interested in investigating the therapeutic potential of the Gi/o-coupled group III mGluRs for the treatment of CNS disorders. Work by Conn lab and other groups has shown that direct activation or allosteric potentiation of several of the group III mGluRs is effective in both modulating basal ganglia circuitry and in reversing movement deficits in preclinical models of Parkinson’s Disease (PD). It has been difficult, however, to develop compounds that are selective for the various mGluRs, readily penetrate the blood brain barrier, and have desirable pharmacokinetic properties. Additionally, traditional receptor agonists can also have problems as drugs in that they can cause excessive receptor activation, desensitization, and tolerance. The promise of mGluR modulation in certain disease states has prompted the search and characterization of agents acting outside of the traditional glutamate interaction domain. These agents, termed positive and negative allosteric modulators, have no little or no functional activity on their own but have the ability to modulate the function of an agonist or antagonist. This strategy is attractive because the majority of mGluR allosteric modulators identified thus far bind to regions of the receptors that are divergent among family members, providing specificity, improved pharmacokinetic profiles, and maintenance of activity-dependent receptor activation.

In conjunction with Vanderbilt’s High Throughput Screening Facility, we are now identifying compounds that act as allosteric modulations of each of the mGluRs. Compounds with activity at the group III mGluRs will be rigorously tested for activity, potency, and selectivity and then, in conjunction with other scientists working with the Conn lab, used as critical tools in electrophysiology and behavioral pharmacology experiments to better understand the roles of mGluRs in general CNS function. In addition, it is hoped that these compounds will eventually provide starting points for clinically relevant drugs providing therapeutic benefit for neurological disorders such as PD.