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. .

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
3R56AI100901-01S1
Application #
8708276
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2013-08-15
Project End
2015-08-14
Budget Start
2013-08-15
Budget End
2015-08-14
Support Year
1
Fiscal Year
2013
Total Cost
$211,875
Indirect Cost
$86,875
Name
New York University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Wei, Fanhua; Zhang, Yuying; Jian, Jinlong et al. (2014) PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Sci Rep 4:7023
Konopka, Jessica; Richbourgh, Brendon; Liu, Chuanju (2014) The role of PGRN in musculoskeletal development and disease. Front Biosci (Landmark Ed) 19:662-71
Wei, Fanhua; Zhang, Yuying; Zhao, Weiming et al. (2014) Progranulin facilitates conversion and function of regulatory T cells under inflammatory conditions. PLoS One 9:e112110
Tian, Qingyun; Zhao, Yunpeng; Mundra, Jyoti Joshi et al. (2014) Three TNFR-binding domains of PGRN act independently in inhibition of TNF-alpha binding and activity. Front Biosci (Landmark Ed) 19:1176-85
Wei, Jianlu; Richbourgh, Brendon; Jia, Tanghong et al. (2014) ADAMTS-12: a multifaced metalloproteinase in arthritis and inflammation. Mediators Inflamm 2014:649718
Tian, Qingyun; Zhao, Shuai; Liu, Chuanju (2014) A solid-phase assay for studying direct binding of progranulin to TNFR and progranulin antagonism of TNF/TNFR interactions. Methods Mol Biol 1155:163-72
Wei, Jianlu; Liu, Chuan-ju; Li, Zongdong (2014) ADAMTS-18: a metalloproteinase with multiple functions. Front Biosci (Landmark Ed) 19:1456-67
Zhao, Yun-peng; Tian, Qing-yun; Frenkel, Sally et al. (2013) The promotion of bone healing by progranulin, a downstream molecule of BMP-2, through interacting with TNF/TNFR signaling. Biomaterials 34:6412-21
Jian, Jinlong; Konopka, Jessica; Liu, Chuanju (2013) Insights into the role of progranulin in immunity, infection, and inflammation. J Leukoc Biol 93:199-208

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