The role of FAST in immune-mediated inflammatory disease

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DESCRIPTION (provided by applicant): The objective of this proposal is to determine the role of FAST (Fas-activated serine/threonine phosphoprotein) in the pathogenesis of immune-mediated inflammatory disease. FAST is overexpressed in peripheral blood cells derived from patients with rheumatoid arthritis and systemic lupus erythematosus. FAST binds to TIA-1, an adenine/uridine-rich element (ARE)-binding protein that inhibits the translation of select pro-inflammatory proteins, including TNF, IL-1, COX-2 and MMP-13. We show that FAST can inhibit TIA-1 mediated translational silencing. FAST also inhibits Fas-induced apoptosis, probably by inhibiting TIA-1 mediated translational silencing of ARE-containing transcripts encoding inhibitors of apoptosis. We hypothesize that FAST contributes to the pathogenesis of immune-mediated inflammatory disease by promoting the expression of pro-inflammatory proteins and inhibiting Fas-induced apoptosis. The specific aims are: 1) To complete a structure:function analysis of the FAST:TIA-1 complex, 2) To determine the effect of FAST on the expression of pro-inflammatory proteins, 3) To determine how FAST regulates apoptosis, and 4) To determine whether FAST modulates immune-mediated inflammatory disease in transgenic mice. We will determine whether FAST promotes the expression of pro-inflammatory proteins in macrophages. We will identify FAST mutants that cannot bind to TIA-1 to determine whether TIA-1 is essential for this function. We will identify the mRNAs encoding inhibitors of apoptosis that are targeted by FAST to inhibit Fas-induced apoptosis. We will determine how interactions with TIA-1 and BCL-XL regulate the function of FAST. Finally, we will generate transgenic mice that overexpress FAST and mutant mice that lack FAST to determine its importance in the initiation and/or propagation of immune-mediated inflammatory disease.