Research Interests
The studies in my laboratory have focused primarily on corticotropin-releasing hormone (CRH). This 41 amino acid neuroendocrine peptide is the key hypothalamic releasing factor in the mammalian stress response. Hypothalamic CRH stimulates the synthesis and secretion of adrenocorticotropin (ACTH) from the anterior pituitary, which in turn stimulates the production and release of glucocorticoids from the adrenal cortex. Glucocorticoids then mediate the body's adaptive response to stress. CRH is also expressed in other regions of the brain and in the periphery where it mediates many of the endocrine, autonomic, and immunological effects of stress. Moreover, alterations in CRH neural activity appear to contribute to a number of illnesses including depression, anxiety disorders, and anorexia nervosa.
One goal of our research is to understand the molecular mechanisms responsible for transcriptional regulation of this important peptide. We have used recombinant DNA approaches and gene transfer methods to localize DNA sequences in the flanking regions of the CRH gene which mediate regulation by different extracellular (neurotransmitters, hormones) or intracellular (second messenger molecules) signals. We have focused on transcriptional regulation of the CRH gene by cAMP, calcium, and steroid hormones. Of particular interest is the differential glucocorticoid regulation of the CRH gene; hypothalamic CRH expression in negatively regulated by glucocorticoids while placental CRH expression is positively regulated by glucocorticoids.
The biological effects of CRH are, of course, dependent upon specific receptors on the post-synaptic or target cells. In addition to the two classes of CRH receptors, a high affinity CRH-binding protein (CRH-BP) was recently isolated. This protein is distinct from the receptors, binds CRH with an affinity equal to or greater than that of the receptors, and is expressed in the pituitary and CNS of rodents and primates. In vitro, this binding protein appears to neutralize the biological activity of CRH and the recently discovered CRH-like peptide, urocortin. These findings have led us to hypothesize that the CRH-BP may play an important physiological role by modulating the biological effects of CRH and other CRH-like peptides in the pituitary and CNS. We are presently characterizing the expression, regulation, and activity of the CRH-BP using in situ hybridization histochemistry, RNase protection assays, gene transfer studies, and biochemical methods. We have also created mouse models for CRH-BP overexpression or deficiency states. CRH-BP deficient mice, created by homologous recombination in embryonic stem cells, show increased anxiety-like behavior and decreased weight gain, consistent with elevated levels of "free" CRH and urocortin in the absence of CRH-BP. The results from these in vivo and in vitro studies will allow us to better understand the role of this protein in modulating the actions of CRH and other CRH-like peptides in the pituitary and within the central nervous system.