The overall objectives of the research project are several: (1) The characterization in vitro and in vivo of a subclass of murine mast cells containing chondroitin sulfate (putative mucosal mast cells) rather than heparin proteoglycan in terms of growth factors, amino acid composition and carbohydrate structure of the peptide core of the proteoglycan, physicochemical characteristics and function of the neutral proteases of the secretory granule, development and utilization of cell-specific monoclonal antibodies for in vivo localization in normal and diseased states of the mouse, and definition of the extracellular functions of the major secretory granule constituents, namely, proteoglycan and neutral protease(s). (2) The selective oxidation of arachidonic acid by the 5-lipoxygenase pathway in cells with proinflammatory function under biologically relevant circumstances such as the introduction into the membrane of fatty acids alternative to arachidonic acid, namely eicosapentaenoic and docosahexaenoic acids from fish-enriched diets, and assessment of responses in murine mast cells and human polymorphonuclear neutrophilic leukocytes; the analysis of the selective recruitment of this pathway in human monocytes responding to particulate activators as compared to immune complexes expressing IgG; the elucidation of the mechanism(s) by which mononuclear cell-derived products, lymphokine(s) and monokine(s), augment leukotriene production in eosinophils responding to an activating stimulus; and definition of the pathway by which endogenous neutral protease of the rat mast cell initiates an activation-secretion response in this cell. (3) The demonstration of the differential distribution, cellular and subcellular, of the subclass-specific receptors for LTC4 and LTD4, in non-vascular smooth muscle and in vascular tissue, endothelial and smooth muscle, and the definition of the post-receptor biochemical events linked to these subclass-specific receptors for the sulfidopeptide leukotrienes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI022531-01
Application #
3133719
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1984-12-01
Project End
1989-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Lam, Bing K (2003) Leukotriene C(4) synthase. Prostaglandins Leukot Essent Fatty Acids 69:111-6
Lam, Bing K; Austen, K Frank (2002) Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes. Prostaglandins Other Lipid Mediat 68-69:511-20
Boyce, Joshua A; Mellor, Elizabeth A; Perkins, Brandy et al. (2002) Human mast cell progenitors use alpha4-integrin, VCAM-1, and PSGL-1 E-selectin for adhesive interactions with human vascular endothelium under flow conditions. Blood 99:2890-6
Castells, M C; Klickstein, L B; Hassani, K et al. (2001) gp49B1-alpha(v)beta3 interaction inhibits antigen-induced mast cell activation. Nat Immunol 2:436-42
Hsieh, F H; Lam, B K; Penrose, J F et al. (2001) T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C(4) synthase expression by interleukin 4. J Exp Med 193:123-33
Bannert, N; Farzan, M; Friend, D S et al. (2001) Human Mast cell progenitors can be infected by macrophagetropic human immunodeficiency virus type 1 and retain virus with maturation in vitro. J Virol 75:10808-14
Mellor, E A; Maekawa, A; Austen, K F et al. (2001) Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells. Proc Natl Acad Sci U S A 98:7964-9
Daheshia, M; Friend, D S; Grusby, M J et al. (2001) Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J Exp Med 194:227-34
Friend, D S; Gurish, M F; Austen, K F et al. (2000) Senescent jejunal mast cells and eosinophils in the mouse preferentially translocate to the spleen and draining lymph node, respectively, during the recovery phase of helminth infection. J Immunol 165:344-52
Lam, B K; Frank Austen, K (2000) Leukotriene C4 synthase. A pivotal enzyme in the biosynthesis of the cysteinyl leukotrienes. Am J Respir Crit Care Med 161:S16-9

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