Nuclear Hormone Receptors

Most of the physiological processes in our bodies are controlled by hormones that can travel large distances prior to entering cells and eliciting changes in gene expression. A large portion of these responses are mediated through a family of proteins called nuclear receptors (NRs). NRs control most of the metabolic pathways in our body as well as related processes such as memory, behavior and aging. Consequently, a large number of human diseases - for example diabetes, obesity and Alzheimers - are caused, or enhanced, by NR malfunctions. Fortunately, the ability of these proteins to respond to small hormonal molecules also makes them ideal drug targets. In fact, a disproportionate percentage of the most successful and important pharmaceuticals and nutraceuticals target NRs. This is despite the fact that hormone partners have yet to be identified for many of them.

We have devised new methods to identify unknown NR hormone small molecule partners. These methods allow us to screen for compounds that may only work in specific cells or tissues. We can also screen for natural compounds that do not cross-react with other NRs or proteins to cause detrimental side effects. Over the past couple of decades we have identified over a dozen new NR ligands that function in numerous tissues from the liver to the brain. Our current focus is on ligands that are produced by the bacteria in our guts. These trigger a wide range of both positive and negative physiological responses by targeting NRs and their corresponding target genes. We now have several dozen new high affinity ligands in our pipeline derived from a variety of natural sources, and are analyzing these for potential use in a variety of metabolic and inflammatory diseases.