ALIGNED RESEARCH FOCUS
Reproductive medicine, neuroscience, metabolism and obesity.
Our studies focus on the molecular, cellular and physiological actions of steroid hormones in the brain. Ovarian estrogens exert critically important actions in specific neuronal populations to regulate ovulatory cyclicity, reproductive behaviors, energy homeostasis and body weight. Estrogen receptor alpha (ERα) appears to mediate most of these effects, as disruption of ERα signaling leads to infertility and metabolic syndrome. ERα signaling mechanisms may include “classical genotropic” effects mediated by direct binding of receptor dimers to DNA, “non-classical genotropic” effects involving tethering of ERs to other transcription factors and “non-classical non-genotropic” actions mediated by cytoplasmic ERs coupled to membrane-initiated signal transduction pathways. Our studies are making use of conditional gene targeting to ascertain the cellular mechanisms by which ERα mediates E2 effects on these physiological and behavioral processes. We have utilized a novel mutant ERα knock-in mouse model, which confers non-classical genotropic and non-genotropic signaling in the absence of classical signaling, to determine that non-classical ERα signaling can convey E2 effects integral to homeostatic feedback control of reproductive hormone secretions, as well as E2 actions governing metabolic function and body weight regulation. We are currently developing viral vector-mediated gene knockdown approaches to probe these important signaling mechanisms in non-human primates.