Audrey Seasholtz, Ph.D.

Associate Director, Doctoral Program in Neuroscience
Professor, Biological Chemistry
Research Professor, Molecular and Behavioral Neuroscience Institute

5035 BSRB, Box 2200

(734) 936-2072

Appointments

Molecular & Behavioral Neuroscience Institute
Biological Chemistry, Medical School
Neuroscience Department, Medical School

Areas of Interest

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.

Honors & Awards

1981 American Chem. Society-Award for Outstanding Student Research and Teaching
1990-1993, 1996-1999 NARSAD-Young Investigator Award
1994 MHRI Distinguished Achievement Award
1999 Career Development Award, UM Agenda for Women
1999-2001 NARSAD Independent Investigator Award
2000 Research Scientist Recognition Award

Published Articles or Reviews

Karolyi, I.J., Burrows, H.L., Nakajima, M., Ramesh, T., Camper, S.A., and Seasholtz, A.F. (1999) Altered anxiety and weight gain in CRH-binding protein deficient mice. Proc. Natl. Acad. Sci, USA 96:11595-11600. PMID: 10500222

Speert, D.B., McClennen, S.J., and Seasholtz, A.F. (2002) Sexually dimorphic expression of CRH-binding protein in the mouse pituitary, Endocrinology 143:4730-4731. PMID: 12446601

Van de Stolpe, A., Slycke, A.J., Reinders, M.O., Zomer, A.W.M., Goodenough, S., Behl, C., Seasholtz, A.F., van der Saag, P.T.:Estrogen receptor (ER)-mediated transcriptional regulation of the human Corticotropin-Releasing Hormone-Binding Protein promoter: differential effects of ERalpha and ERbeta. (2004) Molecular Endocrinology 18:2908-2923. PMID: 15345745

Westphal, N.J. and Seasholtz, A.F. (2005) Gonadotropin-releasing hormone (GnRH) positively regulates CRH-binding protein expression via multiple intracellular signaling pathways and a multipartite GnRH response element in alphaT3-1 cells. Molecular Endocrinology 19: 2780-2797. PMID: 15976007

Westphal, N.J., Seasholtz, A.F. (2006) CRH-BP: the regulation and function of a phylogenetically conserved binding protein. Front Biosci. 11: 1878-1891. PMID: 16368564

Westphal, N.J., Evans, R.T., and Seasholtz, A.F. (2009) Novel expression of type 1 CRH receptor in multiple endocrine cell types in the murine anterior pituitary. Endocrinology 150:260-267. PMID: 18787023

Seasholtz A.F., Ohman, M., Wardani, A., Thompson, R.C. (2009) Corticotropin-releasing hormone receptor expression and functional signaling in murine gonadotrope-like cells. J Endocrinol. 200:223-32. PMID: 19008330

Evans RT, Seasholtz AF. (2009) Soluble Corticotropin-Releasing Hormone Receptor 2{alpha} Splice Variant is Efficiently Translated, but not Trafficked for Secretion. Endocrinology. Jun 11, e-pub. PMID: 19520785