Corticotropin-releasing hormone (CRH) is widely recognized as the key physiological regulator of the mammalian stress response. Within the hypothalamic-pituitary-adrenal (HPA) axis, CR1-I is the principal hypothalamic hormone controlling pituitary ACTH synthesis and release. At other sites in the central nervous system (CNS), CRH is thought to act as a neurotransmitter to mediate the behavioral, autonomic, and immunological responses to stress. The recent characterization of urocortin, a new CR1-I-like ligand in mammals, adds to the complexity of the CRH system. Both CRH and urocortin mediate their endocrine and/or synaptic effects via two classes of CRH receptors. Similarly, both CRH and urocortin bind to the CRH-binding protein (CRH-BP). This secreted binding protein is smaller than the CRH receptors, but binds CRH and urocortin with an affinity equal to or greater than that of the receptors, and blocks CRH-mediated ACTH secretion in vitro. The CRH-BP is expressed in the anterior pituitary and brain of rodents and primates. Some regions of CRH-BP expression colocalize with sites of CRH synthesis or release, suggesting that this binding protein may have a profound impact on the biological activity of CRH as a hypothalamic releasing factor and neurotransmitter. We have hypothesized that the CRH-BP is an important modulator of the actions of CRH and other CRH-like ligands in the pituitary and central nervous system in vivo. Recent studies in our laboratory suggest that gonadal steroids regulate pituitary CRH-BP expression. This sexual dimorphism in CRH-BP expression suggests that the CRH-BP may exhibit new gender-specific modulatory roles in the pituitary and brain. Studies in this proposal will examine the modulatory roles of the CRH-BP by characterizing its regulation in vivo and in vitro and examining its functions in mouse models of altered CRH-BP expression, paying particular attention to sexually dimorphic phenotypes. Studies in Aim I examine the in vivo regulation of pituitary CRH-BP expression by gonadal steroids.
In Aim II, the molecular mechanisms mediating steroid hormone regulation of CRH-BP gene regulation will be examined, focusing principally on the differential regulation by glucocorticoids and positive regulation by estrogen.
In aims 3 and 4, the in vivo roles of CRH-I-BP will be further analyzed using CRH-BP-deficient mice and new transgenic models of targeted, inducible CRH-BP overexpression. As dysregulation of CR1-I activity is thought to play a significant role in major depression, anxiety disorders, and anorexia nervosa, a clearer understanding of the role of CRH-BP in the modulation of activity of CR1-I and other CRH-like ligands may be important to our understanding of the etiology and treatment of these human disease states.
