Description of Invention: National Institutes of Health researchers have developed knockout mice that do not express Tristetraprolin (TTP). TTP is an AU-rich element (ARE) binding protein and the prototype of a family of CCCH zinc finger proteins. AREs were identified as conserved sequences found in the 3’ untranslated region (3’ UTR) of a variety of transiently expressed genes including early response genes, proto-oncogenes, and other growth regulatory genes. AREs function as instability sequences that target ARE-containing transcripts for rapid mRNA decay. TTP functions by binding directly to the ARE sequence contained in the TNF-alpha mRNA, which destabilizes and mediates rapid decay of the TNF-alpha mRNA. More recent studies demonstrate TTP’s ability to downregulate IL-2 gene expression.
TTP knockout mice appear normal at birth but soon develop inflammatory arthritis, dermatitis, cachexia, autoimmunity, and myeloid hyperplasia. Almost all aspects of these phenotypes can be prevented with repeated injections of antibodies to TNF. Moreover, macrophages isolated from these mice exhibit increased production of TNF-alpha and increased amounts of TNF-alpha mRNA.
This transgenic mouse model will be valuable in advancing our understanding of the mechanisms controlling mRNA turnover in immune homeostasis as well as autoimmune diseases. This model will also permit the development of screening assays to elucidate the functions and binding partners for other members of the CCCH zinc finger family as well as compounds capable of inhibiting aberrant TNF-alpha and IL-2 biosynthesis. Lastly, this model will advance understanding of the pathogenetic role for IL-2 and/or TNF in various autoimmune and inflammatory diseases.
Patent Status: Research Material -- patent protection is not being pursued for this technology.
RL Olgivie et al. Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay. J Immunol. 2005 Jan 15;174(2):953-961. [ PubMed abs ]
DM Carrick et al. The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis. Arthritis Res Ther. 2004;6(6):248-264. [ PubMed abs ]
E Carballo et al. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 1998 Aug 14;281(5379):1001-1005. [ PubMed abs ]
Licensing Status: The mice will be made available on a non-exclusive basis under a Biological Materials License Agreement.
Portfolios: Devices/Instrumentation Devices/Instrumentation - Research Tools and Materials Cancer Cancer - Research Materials Internal Medicine Internal Medicine - Research Materials Animal Model
For Additional Information Please Contact: Surekha Vathyam Ph.D. NIH Office of Technology Transfer 6011 Executive Blvd. Suite 325, Rockville, MD 20852 United States Email: email@example.com Phone: 301-435-4076 Fax: 301-402-0220