Post-transcriptional regulation of inflammatory arthritis

Brigham And Women'S Hospital, Boston MA

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Abstract

The objective of this proposal is to determine how TTP and TIA-1 modify the initiation and resolution of[unreadable] inflammatory arthritis. TTP and TIA-1 are RNA-binding proteins that regulate the stability and translation[unreadable] of selected mRNAs that encode pro-inflammatory proteins involved in the pathogenesis of arthritis.[unreadable] Mutant mice lacking TTP and TIA-1 overexress pro-inflammatory proteins and develop spontaneous[unreadable] arthritis. These mice also overproduce bone marrow and peripheral blood neutrophils that aberrantly[unreadable] overexpress TNF. TTP and TIA-1 also modulate arthritis induced by anti-glucose-6-phosphate isomerase[unreadable] (GPI) antibodies. In response to anti-GPI, TTP-/- mice develop arthritis more quickly than wild type[unreadable] controls. Remarkably, the resolution phase of synovial inflammation is markedly accelerated in mice[unreadable] lacking either TIA-1 or TTP. Thus, TTP and TIA-1 are disease modifiers that have profound effects on[unreadable] both the initiation and resolution of synovial inflammation. We hypothesize that these effects result from[unreadable] altered expression of proteins and/or lipid mediators that either promote or inhibit inflammation. We[unreadable] further hypothesize that neutrophils, an important source of both pro- and anti-inflammatory compounds,[unreadable] play a key role in bringing about the modulatory effects of TTP and TIA-1. The specific aims of this[unreadable] propsal are: 1) To determine the role of neutrophils in spontaneous and anti-GPI-induced arthritis in TIA-1-[unreadable] /-TTP-/- mice, 2) To identify neutrophil-derived pro-inflammatory proteins required for synovial[unreadable] inflammation, 3) To determine how TIA-1 and TTP regulate the expression of inflammatory effector[unreadable] molecules in neutrophils, and 4) To determine how TIA-1 and TTP regulate the resolution phase of the[unreadable] inflammatory response. These aims will be accomplished by determining whether neutrophil depletion[unreadable] and/or TNF blockade prevents arthritis in these animals. We will use adoptive transfer experiments to[unreadable] identify neutrophil-derived inflammatory mediators required for synovial inflammation. Finally, we will[unreadable] determine how TIA-1 and TTP regulate the resolution of synovial inflammation.