The complex cellular and molecular interactions that function pathogenically in human synovial inflammatory diseases such as rheumatoid arthritis remain only partially understood. We have recently demonstrated a previously unappreciated critical role for mast cells in the K/BxN serum transfer model of inflammatory arthritis. However, the precise mechanisms by which synovial mast cells are activated and the mediators of inflammation elaborated by this cell population are unknown. This specific goals of this proposal are: 1) to define the mechanisms of synovial mast cell activation and 2) define the inflammatory mediators produced by synovial mast cells that contribute to arthritis. This proposal will utilize both in vitro cellular and molecular techniques and in vivo genetic approaches to elucidate the mechanisms by which synovial mast cells participate in synovial inflammation. These analyses will shed light on pathogenic mechanisms relevant to human inflammatory arthritis such as rheumatoid arthritis. It is likely that further understanding of synovial mast cell participation in arthritis will open new avenues of treatment for these diseases. Furthermore, these studies will expand our understanding of mast cell biology in inflammatory responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059746-03
Application #
7033878
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Peyman, John A
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$340,897
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Douaiher, Jeffrey; Succar, Julien; Lancerotto, Luca et al. (2014) Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol 122:211-52
Hamilton, Matthew J; Frei, Sandra M; Stevens, Richard L (2014) The multifaceted mast cell in inflammatory bowel disease. Inflamm Bowel Dis 20:2364-78
Prieto-García, A; Castells, M C; Stevens, R L (2014) Mast cell-derived htryptase-beta functions as a potent anticoagulant by proteolytically damaging fibrinogen. J Investig Allergol Clin Immunol 24:286-7
Prieto-García, Alicia; Castells, Mariana C; Hansbro, Philip M et al. (2014) Mast cell-restricted tetramer-forming tryptases and their beneficial roles in hemostasis and blood coagulation. Immunol Allergy Clin North Am 34:263-81
Hansbro, Philip M; Hamilton, Matthew J; Fricker, Michael et al. (2014) Importance of mast cell Prss31/transmembrane tryptase/tryptase-? in lung function and experimental chronic obstructive pulmonary disease and colitis. J Biol Chem 289:18214-27
Beckett, Emma L; Stevens, Richard L; Jarnicki, Andrew G et al. (2013) A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis. J Allergy Clin Immunol 131:752-62
Magarinos, Natalia J; Bryant, Katherine J; Fosang, Amanda J et al. (2013) Mast cell-restricted, tetramer-forming tryptases induce aggrecanolysis in articular cartilage by activating matrix metalloproteinase-3 and -13 zymogens. J Immunol 191:1404-12
Adachi, Roberto; Krilis, Steven A; Nigrovic, Peter A et al. (2012) Ras guanine nucleotide-releasing protein-4 (RasGRP4) involvement in experimental arthritis and colitis. J Biol Chem 287:20047-55
Kaieda, Shinjiro; Wang, Jun-Xia; Shnayder, Ruslan et al. (2012) Interleukin-33 primes mast cells for activation by IgG immune complexes. PLoS One 7:e47252

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