My lab's research seeks to understand the mechanism of action of the hormone melatonin at the MT1 and MT2 G-protein coupled receptors. We study these receptors in the brain and through the body with the goal of identifying ligands that exhibit useful binding affinity and therapeutic potential. Our team of undergraduate and graduate students, postdoctoral fellows, technicians and senior scientists work with each other and with expert co-investigators in medicinal chemistry to discover and develop novel molecules that can mimic or counteract the actions of melatonin. These molecules may help treat a variety of diseases and conditions including insomnia, circadian sleep disorders, depression, seasonal affective disorders, and cardiovascular disease.

Our laboratory pursues these investigations from several angles. We assess the localization of the melatonin receptors, examine their cellular and molecular signaling mechanisms,and investigate receptor fate following prolonged exposure to melatonin. We study the distinct roles of selective MT1 and MT2 melatonin receptor ligands in modulating circadian rhythms, methamphetamine's ability to induce both sensitization to prolonged exposure, and stimulation of the reward system. We also study cell proliferation, survival, and neurogenesis in the brain, and the changes in gene expression underlying all these processes.

Our research ultimately aims to discover novel drugs with differential actions at the MT1 and MT2 receptors. We use molecular-based drug design, computer modeling and medicinal chemistry to design and synthesize small molecules that target these receptors as agonists, inverse agonists and/or antagonists. We then pharmacologically and functionally characterize these molecules using cell-based assays and bioassays and test them in circadian and behavioral animal models.

My laboratory researches complementary aspects of host-pathogen interactions through two distinct projects in the fields of immunology and bacterial pathogenesis.

In the field of immunology, we study the cellular and molecular mechanisms that regulate mucosal immune responses by stimulating the immune system with enterotoxins produced by certain strains of E. coli. Mucosal immune responses provide critical protection against microbial pathogens that invade through the body’s mucosal surfaces (the gut, the oral cavity, the urogenital system, and the respiratory system). The enterotoxins we employ are potent mucosal adjuvants which enhance mucosal and systemic immune responses to foreign antigens when administered concurrently. In addition to describing these immune regulation mechanisms that respond to the enterotoxins, our research can also support the development of new mucosal vaccines.

In the field of bacterial pathogensis, our research analyzes the genetic factors in four pathogenic species of the Bordetellae that enable these microorganisms to scavenge iron from host tissues. The ability of these bacterial pathogens to infect a host depends upon the bacteria acquiring iron from that host using receptors and accessory proteins encoded by specific gene clusters, including hurIR-bhuRSTUV and ecfIR-bfrH. Extracellular signals control expression of these gene clusters by regulating specific sigma factors (ECF). Information obtained in these experiments will provide the means to create drugs to abrogate acquisition of iron, an essential nutrient, and identification of new antigens that can be employed as vaccine targets.