Interactions between the immune, nervous and endocrine systems during the response to stress are key to understanding the immunopathology of stress-associated disease. Such understanding requires identification of the principle targets in the stress response as well as the molecular details Of how information is transferred between these mutually regulating systems. The neuroendocrine stress peptide, corticotropin-releasing hormone (CRH) is the primary mediator of the neuroendocrine stress response and has recently been shown to play a central role in the associated immunomodulation. The focus of this proposal is to understand the role of CRH, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. We shall employ a transgenic animal model of CRH overproduction and chronic hypothalamicpituitary-adrenal activation, which provides the first genetic model of stress-associated immunomodulation. We have shown these transgenic mice to display the behavioral features associated with stress as well as Cushing's syndrome and immune dysfunction. Using this genetic animal model and a second provided by our collaborator Dr. R. Allen, which bears an inducible ACTH """"""""knockout"""""""", I propose to examine the relative contributions of CRH and the direct downstream neuroendocrine products of CRH stimulation, namely, ACTH and glucocorticoids in modulating B lymphocyte development and function in chronic stress. We also propose to examine the role of peripheral catecholamines in this system. In this proposal, we shall test the hypothesis that CRH overproduction leads to loss of B lymphocytes and decreased immune responsiveness.
The specific aims are: 1) To determine the mechanism of B lymphocyte loss in CRH-overproducing mice. 2) To determine the mechanism of increased susceptibility to infectious disease and altered B lymphocyte function in CRH-overproducing mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH055722-03
Application #
2890799
Study Section
Special Emphasis Panel (ZMH1-BRB-T (01))
Program Officer
Winsky, Lois M
Project Start
1997-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239