Thomas J. Baranski, M.D., Ph.D.

DEPARTMENT OF Internal Medicine
Keywords: diabetes, Drosophila, G protein, hormones, protein structure, signal transduction

Our laboratory studies signal transduction by G protein-coupled receptors, a superfamily of heptahelical transmembrane proteins. The receptors act as elegantly engineered switches, receiving signals involved in many physiologic processes — blood pressure regulation, glucose homeostasis, sight and smell — to turn on specific signaling cascades within cells. Remarkably, we devote more than 3 percent of our entire genome to encoding these receptors. Despite their widespread importance, we do not understand how the receptors actually function as ligand-activated switches.

We use engineered yeast to apply the power of genetics to the study of signaling by human G protein-coupled receptors. In one strategy, we use saturation mutagenesis to force segments of a chemoattractant receptor to evolve at an extremely high rate. We have generated the largest set of functional mutations within any G protein-coupled receptor. Combined with bioinformatic approaches, this data allows us to build higher-resolution models of the receptor structure. Insights into how ligands activate receptors will aid in drug design and greatly impact medicine; more than half of currently prescribed pharmaceuticals target G protein-coupled receptors.

A new project in the lab focuses on the mechanisms of insulin resistance that are induced by high sugar diets. To understand why hyperglycemia leads to complications of diabetes mellitus, we generated a simple model in Drosophila melanogaster in which high-sugar feeding leads to developmental and metabolic phenotypes. We will use the genetic power of flies to dissect the molecular pathways that are activated by high sugar feeding and that lead to metabolic derangements.