Allergic asthma is characterized by airway hyper-reactivity (AHR), eosinophilia, and excessive mucus production. Evidence indicates that Th2 differentiated CD4+ T-cells mediate this phenomena. Recently, we have learned that IL-4 and IL-13 are the important products of Th2 cells which act on resident cells of the lung to induce AHR and mucus production in mice. Furthermore, IL-4 receptor alpha (IL-4r-alpha) deficient mice were protected of Th2 cells which act on resident cells of the lung to induce AHR and mucus production in mice. Furthermore, IL-4 receptor-alpha (IL-4r-alpha) deficient mice were protected from these effects. Therefore, the direction of future research has been narrowed to the role of IL-4-alpha mediated intracellular signaling in, as yet unidentified, resident cells of the lung. Ligation of IL-4r-alpha results in activation STAT6 and IRS2 intracellular signaling molecules. It is known that STAT6 is important in mediating most of the known effector functions of IL-4 and IL-13, including Th2 differentiation. Therefore, it is our hypothesis that STAT6 signaling in airway smooth muscle and epithelial cells is important in the development of AHR and mucus production. To address this hypothesis, we propose to expand the use of our STAT6. In particular, we will transfer Th2 cells to wildtype and STAT6-/- mice prior to antigen challenge and airway physiology measurements. Also, we will generate and similar phenotype airway smooth muscle and epithelial cell-specific STAT6 transgenic mice on a STAT6-/- mice prior to antigen challenge and airway physiology measurements. Also, we will generate and similarly phenotype airway smooth muscle and epithelial cell-specific STAT6 transgenic mice on a STAT6-/- genetic background.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL010319-01
Application #
6062395
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
2000-03-01
Project End
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
1
Fiscal Year
2000
Total Cost
$32,416
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143