Tumor necrosis factor (TNF) is a cytokine produced by macrophages and is implicated in the pathogenesis of septic shock and rheumatoid arthritis. An excellent system to study the signal transduction pathways involved in TNF biosynthesis is the lipopolysaccharide (LPS)- induced macrophage system. LPS activates macrophages and causes the release of toxic cytokines including TNF. The signaling pathways utilized by LPS to induce TNF biosynthesis are largely unknown but are believed to be dependent on the activation of tyrosine kinases and the subsequent activation of the three best described MAPK (mitogen activated protein kinase) pathways: MAPK/ERK (mitogen activated protein kinase/extracellular signal regulated kinase), p38, and the JNK/SAPK (Jun N-terminus kinase/stress activated protein kinase) pathways. Furthermore, these signaling pathways branch to regulate both transcription of the TNF gene and translation of TNF. The main objectives of this proposal are to determine the MAPK pathways involved in LPS signaling and to examine their involvement in the transcription and translation of TNF. This will be accomplished using kinase activation assays and transient transfection assays with various signaling molecule expression constructs and TNF transcriptional and translational reporter constructs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM018550-03
Application #
2734344
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1998-07-01
Project End
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390