OHSU

Scanlan Lab

Thyroid Hormone

Our research on thyroid hormone action is focused on the development of thyroid hormone receptor (TR) isoform-selective ligands. There are two genes that encode two different TR's (TRa and TRb), and these genes are further processed at the mRNA level giving rise to an ensemble of four TR isoforms (TRa1, TRa2, TRb1, TRb2) that are expressed at different ratios in different tissues. The phenotypes of targeted gene knock-out mice indicate that these isoforms mediate specific processes in thyroid hormone regulation, although thyroid hormone shows no selectivity for the different isoforms. We have developed a thyroid hormone analog, called GC-1, that is selective for the TRb isoforms and is proving to be a valuable pharmacological probe for addressing the question of the specific roles of the TR isoforms. We have also recently used the GC-1 structural core to synthesize a thyroid hormone antagonist that blocks thyroid hormone action in vivo. This is the first example of a thyroid hormone antagonist, and this will also be an important probe to study thyroid hormone action. Our long term goal is to develop a set of selective thyroid hormone analogs that can activate or inhibit all of the different TR isoforms. These tools will allow us to fully understand the actions of thyroid hormone and will serve as prototypes for selective therapeutics for the treatment of a large number of diseases that intersect with thyroid hormone signaling pathways.

Steroid Hormone

The specific steroid hormones we study are estrogen and the glucocorticoids. The glucocorticoids are members of the larger 3-keto steroid family that includes mineralocorticoids, androgens and progestins, whereas estrogen is structurally distinct from these and is the only steroid hormone that contains an aromatic A-ring. Like thyroid hormone, all of the steroid hormones function as ligands for specific nuclear receptors. The estrogen receptors (ERa and ERb) and the glucocorticoid receptors are good models for studying the aspect of DNA response element selectivity, and how this selectivity can be controlled by ligand structure. With the ER and GR steroid receptors we are studying interesting regulatory effects of non-steroidal ligands at different hormone response elements. The simple (or classical) response element for these steroidal receptors is an inverted hexanucleotide DNA repeat which acts as a binding site for a liganded ER or GR homodimer; receptor binding to this DNA element is an essential first step for transcription initiation. More recently several non-classical response elements that regulate ER and GR action have been discovered, and current thinking suggests that these different response elements may be important in different cell types providing a molecular basis for the tissue specificity of GR , ER and all nuclear receptor ligands. We have prepared a number of non-steroidal ER ligands that show both agonist and antagonist transcription function at a non-classical estrogen response element based on an AP-1 enhancer site. We are now using these ligands as probes to identify the essential factors that mediate transcription from this site. We have initiated similar studies with the GR using novel non-steroidal ligands that we have recently developed.