IL-4 is an essential cytokine in the immune response, regulating T cell differentiation, B cell immunoglobulin production, and the activation of macrophages. These activities give IL-4 a pivotal role in allergic disease. IL-4 acts through binding to the IL-4 receptor (IL-4R), composed of IL-4Ra and the common gamma chain, gc. The results of IL-4 signaling on target cells can be broadly characterized as growth or gene regulation, activities, which are predominantly controlled by two distinct domains of IL-4Ra. Many IL-4-induced gene expression events require the activation of STAT6, which is regulated by the IL-4Ra Gene Regulation Domain. Our work is focused on understanding how IL-4Ra activates STAT6 and the result of this activation on target cell signaling events. The first specific aim is to structurally characterize the IL-4Ra Gene Regulation Domain, through mapping of this domain's minimal STAT6 activation sequence, determining the mobility of this sequence, and ascertaining the essential nature of this sequence in IL-4-mediated gene expression. The second and third specific aims will determine the role of STAT6 in IL-4- mediated negative signaling of mast cells and macrophages using STAT6- deficient mice. These experiments will yield a greater understanding of the structure-function relationship if IL-4Ra and STAT6, and an understanding of these functions in cell signaling and allergic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043433-04
Application #
6510861
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Plaut, Marshall
Project Start
1999-03-01
Project End
2004-02-29
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
4
Fiscal Year
2002
Total Cost
$200,060
Indirect Cost
Name
Virginia Commonwealth University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Harris, Amanda L; Ryan, John J; Farrell, Nicholas (2006) Biological consequences of trinuclear platinum complexes: comparison of [[trans-PtCl(NH3)2]2mu-(trans-Pt(NH3)2(H2N(CH2)6-NH2)2)]4+ (BBR 3464) with its noncovalent congeners. Mol Pharmacol 69:666-72
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Norozian, Farnaz; Kashyap, Mohit; Ramirez, Carlos D et al. (2006) TGFbeta1 induces mast cell apoptosis. Exp Hematol 34:579-87
Kashyap, Mohit; Bailey, Daniel P; Gomez, Gregorio et al. (2005) TGF-beta1 inhibits late-stage mast cell maturation. Exp Hematol 33:1281-91
Gomez, Gregorio; Ramirez, Carlos D; Rivera, Juan et al. (2005) TGF-beta 1 inhibits mast cell Fc epsilon RI expression. J Immunol 174:5987-93
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Mann-Chandler, Meredith N; Kashyap, Mohit; Wright, Harry V et al. (2005) IFN-gamma induces apoptosis in developing mast cells. J Immunol 175:3000-5
Bouton, L Andrew; Ramirez, Carlos D; Bailey, Daniel P et al. (2004) Costimulation with interleukin-4 and interleukin-10 induces mast cell apoptosis and cell-cycle arrest: the role of p53 and the mitochondrion. Exp Hematol 32:1137-45

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