Ulcerative colitis and Crohn's disease are chronic, relapsing inflammatory disorders of the gastrointestinal tract, collectively known as Inflammatory Bowel Disease (IBD). The cause of IBD, which in the U.S. affects an estimated 1.4 million individuals, remains largely unknown. Pro-inflammatory cytokines are believed to play important roles in the pathogenesis of IBD. Among these cytokines, tumor necrosis factor (TNF) has received the greatest attention because of its position at the apex of the inflammatory and immune-regulatory cascades. TNF inhibitors, such as Remicade and Enbrel, have been accepted as an effective approach to treating various kinds of inflammatory diseases, including Crohn's disease and ulcerative colitis. However, their side effects and high cost prompt investigations into new, alternative treatment modalities. One such alternative is a long- known anti-inflammatory growth factor, progranulin (PGRN), which was only recently discovered to be a novel ligand of TNF receptors (TNFR) in our global genetic screen. We recently reported that PGRN antagonizes TNF activity and significantly attenuates or ameliorates experimentally induced inflammatory arthritis in mice. More importantly, Atsttrin, an engineered protein composed of three PGRN fragments, exhibited highly potent anti-inflammatory activity, which surpassed PGRN itself, in vivo. Using PGRN deficient mice, we demonstrated in our preliminary studies that the deletion of the PGRN gene renders B6 mice more susceptible to Dextran Sulfate Sodium (DSS) induction and to developing more severe colitis. In addition, PGRN antagonizes TNF?- mediated down-regulation of Treg suppressive function and Foxp3 expression;in vivo treatment with PGRN selectively stimulates IL-10 production in Treg cells and PGRN-stimulated Treg suppressive function is largely lost if IL-10 signaling is blocked. These studies have led to the central hypothesis that PGRN exerts its protective effects through its interaction with TNFR and the stimulation of IL-10 producing Treg cells in the course of inflammatory bowel disease. This hypothesis will be tested in three Specific Aims: (1) Do PGRN-mediated signaling and molecular events depend on PGRN's interaction with TNF/TNFR in Tregs and in inflammatory bowel disease? (2) Is IL-10 a critical mediator of PGRN action in the pathogenesis of inflammatory bowel disease? (3) Can recombinant PGRN, especially its derived Atsttrin, be directly applied to treat inflammatory bowel disease? Successful completion of the proposed research will not only benefit our understanding of the pathogenesis of IBD, but also lead to the development of new anti-TNF/TNFR therapeutic interventions for various kinds of TNF-related diseases, including IBD. .
In this application we propose to determine the therapeutic effects of progranulin, especially its derived engineered Atsttrin, in treating inflammatory bowel diseases (IBD), as well as the molecular mechanism underlying PGRN-mediated protective function in IBD. In addition, progranulin and its derivatives may also offer new therapeutic interventions for other TN?-associated diseases such as systemic lupus erythematosus, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis.
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