Nuclear Hormone Receptors

    Hormones are chemicals that circulate within the body and trigger specific responses in target tissues. Steroids, such as the estrogens used to treat or postpone menopause and the muscle building steroids taken by some athletes, are a well known example of these. These particular hormones penetrate cells and elicit responses by binding to a family of proteins called nuclear hormone receptors (NHRs). NHRs control many of the metabolic pathways in our body as well as related processes such as memory, behaviour and aging. Consequently, a large number of human diseases - for example diabetes, obesity and Alzheimers - are caused, or enhanced, by NHR malfunctions. Fortunately, the ability of these proteins to respond to small molecules that move efficiently within the body makes them ideal drug targets. In fact, a disproportionate percentage of the most successful and important pharmaceuticals target specific NHRs.

    This is despite the fact that hormone partners have yet to be identified for more than half of NHRs.

We have devised new methods to identify the unknown hormone partners in live animals. These methods allow us to screen for compounds that may only work in specific cells or tissues. We can also screen for compounds that do not cross-react with other NHRs, act in the wrong tissues or cause detrimental side effects. These are common problems in drug discovery that usually only come to light during subsequent clinical trials. These studies began with initial studies on the orphan nuclear receptor FTZ-F1 (Guichet et al, 1997 ;Schwartz et al, 2001). We have since published results (Reinking et al, 2005) showing that the Drosophila receptor E75 uses heme as a constitutive ligand, which in turn allows it to respond to the signaling gas Nitric oxide. In the animal, this allows it to coordinate metabolism with timed processes such as circadian rhythm and metamorphosis (Caceres et al, 2011). Not surprisingly, we have found that the human orthologues of E75, called Rev-erb alpha and beta, also bind heme and respond to Nitric oxide (Pardee et al, 2009). Current efforts are focused on the PPAR family of receptors, which are targets of powerful, albeit sometimes dangerous, drugs used to treat metabolic disorders such as type II diabetes.