This Program Project represents a competitive renewal of a U19 AAIDCRC Award. The unifying theme of each of the four Projects is to identify genetic, immune and environmental factors that modulate asthma disease severity. Project 1 extends Dr. W. Cruikshank?s work on the importance of IL-16 as an asthma disease modifier in mice through the use of IL-16-/- mice and radiation chimera made sufficient with bone marrow from IL-16+ mice; determines the mechanism of T helper (Th)2 cytokine activation of epithelium to synthesize the immunomodulatory cytokine, IL-16; and identifies the functional significance of a SNP in the IL-16 promoter. Dr. M. Fenton heads an entirely new Project 2 which studies the role of environmental lipopolysaccharide (LPS) in the development of airway hyper- reactivity to methacholine in mice through the use of LBP-/-, CD14-/-, and TLR4-/- mice and seeks to determine why aerosol antigen challenged LPS binding protein (LBP)-/- mice lack airway hyper-reactivity (AHR) nitric oxide (NO) production. Project 3 is a renewal of Dr. A. Fine's work on the role of Fas mediated apoptosis in the evolution and resolution of airway inflammation in mouse models of inflammation and determines the mechanisms that control localization of Fas in bronchial epithelial cells. Project 4 is headed by Drs. D. Center and G. O'Connor. This new clinical project proposes to test the hypotheses generated by Project 1 that IL-16 is transcriptionally regulated in epithelium following exposure to Th2 cytokines and acts as a disease modifier by negative feedback on both the immune and inflammatory components of the airway inflammation. The project will correlate promoter genotype with asthma phenotype and IL-16, IL-9 and IL-13 serum levels. Projects 1, 2 and 3 are assisted by an animal genetics Core A headed by Dr. A. Marshak-Rothstein which provides a central facility for breeding all animals, immunization and challenge for physiology and tissue fixation for evaluation of inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI050516-02
Application #
6534370
Study Section
Special Emphasis Panel (ZAI1-NBS-I (M3))
Program Officer
Adams, Ken
Project Start
2001-09-24
Project End
2006-06-30
Budget Start
2002-09-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$804,084
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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