Neuroimmune communication has been implicated in both physiological defense against infection and pathogenic events contributing to many disorders of the central nervous system (CNS). A key mediator for this communication is interleukin-1. The following evidences indicate IL-1 acts on cells of the blood brain barrier to affect the CNS: 1) The functional 1L-1 receptor (type I IL-1 receptor, IL-1r1) is mostly expressed on CNS endothelial cells, 2) IL-1-responsive immediate early gene IkappaBalpha is induced primarily in CNS endothelium after central IL-1 injection; 3) inflammatory mediators such as the prostaglandins are induced in brain endothelial cells after both peripheral and central immune challenges; and 4) IL-1r1 is essential for mediating the recruitment of leukocytes across the BBB during the development of CNS immune responses. The central hypothesis of this proposal, therefore, is that IL-1 affects the CNS through the activation of CNS endothelial cells. This hypothesis can be tested directly in our recently created transgenic mice with which we can specifically inhibit the expression of IL-1r1 on endothelial cells. The long range goal of this application is to elucidate the role of BBB in mediating neuroimmune crosstalk. Using these transgenic animals, the following specific aims will be tested: 1) Determine the distribution of IL-1r1 protein expression in the CNS in normal and immunologically challenged mice. 2) Determine the role of endothelial IL-1r1 in mediating the activation of the neural circuits and the functional consequences induced by peripheral and central immune challenges. 3) Determine the role of endothelial IL-1r1 in the recruitment of leukocyte across the BBB. 4) Determine the role of endothelial IL-1r1 in mediating the development and progression of experimental autoimmune encephalomyelitis (EAE). The results of this project should provide a definitive analysis to determine the role of endothelial IL-1r1 in several aspects of neuroimmune interaction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI059089-01A1
Application #
6867079
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Johnson, David R
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
1
Fiscal Year
2005
Total Cost
$299,000
Indirect Cost
Name
Ohio State University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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