Allergic diseases are characterized by overproduction of Th2- cytokines. We have recently shown that the provision of three distinctive proteins, the c-maf protooncogene, the transcription factor Nuclear Factor of Activated T Cells (NFAT), and a novel nuclear antigen NIP45, confers on a non-producer cell the ability to produce IL-4. The phenotypes of c-maf and NFAT genetic mutant mice recently produced in our laboratory provide compelling evidence that c-maf and NFAT proteins control the Th2 differentiative program. However, many questions remain about how the interaction of c-maf and the NFAT family of transcription factors controls IL-4 gene transcription. For example, the striking Th2 phenotype of mice that lack both the NFATp and NFAT4 factors raises new questions about the mechanism by which NFAT factors control the development and activation of Th2 cells. In this proposal we aim to further explore the molecular mechansims by which NFAT and c-maf control IL-4 gene transcription and Th2 differentiation in general. We also wish to definitively test the role of these factors in allergic airway disease in vivo by taking advantage both of NFAT and c-maf genetic mutant mice already generated by us, and by the creation of a conditional c- maf null mutant. We will address the following questions. What is the nature of acute and chronic allergic airway disease in c- maf and NFAT genetic mutant mice? Does the conditional ablation of c-maf in vivo alter the production of Th2 cytokines and allergic airway disease? What genes, in addition to the cytokines, are regulated by NFATp and NFAT4? Are there c-maf interacting proteins, in addition to NFAT, that are important for IL-4 production? We anticipate that our experiments will establish the critical role of NFAT and c-maf factors in allergic disease and will lead to the discovery of additional c-maf interacting proteins and NFAT target genes that control Th2 differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI031541-12
Application #
6657464
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2002-09-01
Project End
2003-08-31
Budget Start
Budget End
Support Year
12
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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