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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK042730-10A1
Application #
6333543
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
1990-12-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
10
Fiscal Year
2001
Total Cost
$251,345
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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