Although there have been significant recent gains into our understanding of what causes Inflammatory Bowel Disease (IBD), there are voids in our knowledge and treatment options may be limited for certain patients. The mast cell is an effector immune cell that resides in the intestine and plays an important role in innate immunity. Although it has been thought to be important based on its increased presence in inflamed segments of intestinal tissue, its role is largely unknown. I have determined that a mediator released from activated mast cells, mouse mast cell protease-6 (mMCP- 6), plays an essential pro-inflammatory role in chemically-induced colitis in mice. The human ortholog to mMCP-6 is Tryptase-?1 which is the dominant mast cell tryptase in humans. Based on published studies from our group and my preliminary data, I hypothesize that mMCP-6 acts to alter the permeability of the epithelial barrier and to bring neutrophils to the site of inflammation. I willuse strains of mice we have created to lack expression of mMCP-6 in various colitis models, in vitro studies using cultured mast cells and epithelial cells, and recombinant mouse and human mast cell tryptase to extensively study the mechanism of action of mast cell tryptase in colitis. I also will test an inhibitor of mMCP-6 which may have future therapeutic significance for patients with IBD. I will perform these studies in an Institution where every resource is available to me including facilities, mentors, collaborators, and advisers. In this environment and with the guidance of my mentors and collaborators, I will be poised to attain my goal of becoming an independent investigator.

Public Health Relevance

Mast cells are important in allergy but they are also important to protect us from infections. Mast cells can release a substance called tryptase that I have found makes inflammation worse in certain mouse models of colitis. I propose an in depth study to see how mast cell tryptase works which will lead to new understanding for what drives inflammation in patients with Inflammatory Bowel Disease. Furthermore, I will test a drug that is designed to block the effects of mast cell tryptase and could provide a novel treatment option to treat colitis.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK094971-03
Application #
8721406
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Allegretti, Jessica R; Hamilton, Matthew J (2014) Restoring the gut microbiome for the treatment of inflammatory bowel diseases. World J Gastroenterol 20:3468-74
Doyle, Leona A; Sepehr, Golrokh J; Hamilton, Matthew J et al. (2014) A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 38:832-43
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
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
Cardet, Juan-Carlos; Castells, Mariana C; Hamilton, Matthew J (2013) Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep 13:10-8