Interleukin-12 is a pivotal cytokine representing the link between the cellular and humoral branches of an effective host immune defense apparatus. It is a key factor in the induction of T-cell dependent and independent activation of macrophages, generation of T helped type 1 and cytotoxic T cells, resistance to bacterial and parasitic infections, and elimination of tumors. IL-12 is a heterodimer consisted to two subunits, p40 and p35 that are encoded on different human chromosomes. The expression of these two genes are highly coordinated to form the biologically active IL-12 during an effective immune response. However, under some pathological conditions IL-12 is dysregulated, resulting either in a lack of resistance to microbial infection and uncontrolled tumor growth, or in destructive inflammation. We hypothesize that a transient or irreversible dysregulation of IL-12 production reflects a pathogen/tumor cell-induced disruption in the highly coordinated expression of p40 and p35 genes. This proposal is aimed at: (1) identifying and characterizing the transcription factors which activate factors which activate IL-12 p40 gene expression in response to pathogenic stimulation; (2) investigating the molecular mechanisms of IL-12 p40 gene expression in response to pathogenic stimulation; (2) investigating the molecular mechanism of IL-12 p40 gene expression in T, B and monocytic cells; (3) analyzing the molecular basis of inhibition of IL-12 gene expression by immunosuppressive agents. The understanding of the molecular mechanisms governing the expression of IL-12 p40 and p35 genes in the context of interactions between pathogens and the immune system will benefit significantly our efforts in designing therapeutic strategies to treat infectious and malignant diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA079772-04
Application #
6513421
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
1999-03-10
Project End
2004-02-29
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
4
Fiscal Year
2002
Total Cost
$158,100
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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