Exploring the role of an evolutionary conserved anti-inflammatory protein in Drosophila and mice

Persistent inflammation is a pathogenic determinant in many common human diseases, including rheumatoid arthritis, Crohn’s disease, multiple sclerosis, and psoriasis, while playing a key role in the development of type-2 diabetes, obesity, certain forms of cancer, and neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases. The laboratory of Dr. Blackshear has identified tristetraprolin (TTP) as a protein that acts to restrict inflammation in mice by destabilising the mRNA of pro-inflammatory cytokines such as TNF, GM-CSF, CXCL1 and CXCL2. Mice where an instability-conferring element within TTP’s own mRNA was deleted using homologous recombination were remarkably resistant to inflammatory disease. Most importantly, these mice did not exhibit any pathology, presumably because of the relatively modest over-expression of TTP that was otherwise subject to normal regulation.  

However, studies of TTP’s biochemical and molecular activities have been hampered by the existence of three other members of the same protein family in the mouse.  Each of these proteins exhibits similar biochemical activities in cell transfection experiments and in cell-free assays, but knockout mice of each have led to dramatically different phenotypes, involving early development, hematopoiesis, and placental function rather than inflammation.  For this reason, we will use the fruit-fly Drosophila melanogaster, which expresses only a single TTP family member, known as TIS11. Using genetics, biochemistry, transcriptomics, and proteomics we will explore the role of TIS11 and extrapolate findings to experiments in mammalian systems at NIEHS.