CRHBP's role in mediating HPA/HPG interactions

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Physical and psychological stress are known to activate the hypothalamic-pituitary-adrenal (HPA) axis; however, stress has also been shown to negatively impact the HP-gonadal (HPG) axis. Studies have demonstrated that Corticotropin-Releasing Hormone (CRH), the key hypophysiotrophic effector molecule of the HPA axis, plays a significant role in stress-induced inhibition of reproduction. While CRH is known to act centrally, regulation may exist at the pituitary. CRH binds two receptors and a CRH binding protein (CRHBP), a 37kD glycoprotein thought to be an important modulator of CRH activity. Both CRH-receptors and CRHBP have recently been localized to murine gonadotrope, the primary pituitary cell type involved in reproductive signaling. This localization and the dramatic GnRH-induced increases in CRHBP expression in gonadotrope-like cells suggest that the gonadotrope should be reexamined as a potential site for HPA/HPG interactions and that CRHBP may play an important role in modulating these interactions. This proposal will examine GnRH regulation of endogenous CRHBP expression, molecular mechanisms mediating GnRH induced CRHBP gene regulation, and CRHBP modulation of CRH/HPG interactions in gonadotrope. An understanding of how reproductive hormones regulate CRHBP expression and how CRHBP modulates CRH activity will be important for our understanding of diseases involving CRH dysregulation, including deoression anorexia, anxiety and reproductive disorders.