One major area of study in the laboratory began with the cloning of a gene that was rapidly induced by insulin. The protein encoded by this gene, known as TTP, is the prototype of a novel class of CCCH zinc finger proteins. TTP is rapidly induced, translocated from the nucleus to the cytosol, and phosphorylated on serine residues by insulin and by many other mitogens and growth factors. Mice deficient in this protein develop a complex syndrome consisting of arthritis, wasting, dermatitis, and early death; more recent work has identified an excess of tumor necrosis factor (TNF)as the cause of most if not all aspects of the syndrome. TNF is over-produced by macrophages derived from these knockout mice, due to an increase in the stability of its mRNA. We recently determined that TTP, as well as two related proteins, caused instability of TNF by binding directly to its mRNA, leading in some way to its rapid degradation. Current studies are attempting to determine the mechanisms of this effect, as well as attempts to utilize this novel pathway regulating TNF expression as a target for new drugs for the treatment of TNF excess diseases, such as rheumatoid arthritis, Crohn's disease, AIDS, cancer and others. In addition, polymorphisms in the TTP gene and related genes have been determined through the NIEHS Environmental Genome Project, and studies are beginning that will attempt to correlate these changes with phenotype.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES090080-03
Application #
6432423
Study Section
(LST)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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