The lab uses orphan nuclear receptors to elucidate novel hormonal signaling pathways that participate in normal physiological processes and in disease states. Orphan receptors are structurally related to classical nuclear hormone receptors that mediate the action of steroid, thyroid and retinoid hormones. However, unlike these classical receptors, the ligands for orphan receptors have yet to be identified. Thus, orphan receptors represent unique molecular tools that can be exploited in the search for novel hormonal signals.
Our work has led to the discovery of previously unanticipated regulatory molecules including bile acids, sterols, androstans, eicosanoids and xenobiotics. Most notably, we have identified exciting new compounds that regulate fat cell formation, insulin sensitivity and cholesterol homeostasis. Other orphan nuclear receptors have been linked to Parkinson's disease, cancer and other diseases. Thus, these receptors are defining exciting new areas of research which have significant implications for both basic research and for the design of new drug therapies.
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Schematic illustration of a nuclear receptor dimer activating transcription. The DNA-binding domains of RXR (light blue) and a partner receptor (Rec, green) are shown contacting the hormone response element (HRE, yellow arrows).The ligand-binding domain contains a cavity or pocket that specifically recognizes the cognate ligand (red). When a hormone or ligand is bound within this pocket, the receptor undergoes a conformation change that reorients the position of the transcriptional activation domain (yellow oval). This reorientation allows the receptor to recruit coactivator complexes (pink) thus switching the receptor into a transcriptionally active state.