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Human tryptase gene expression: role in COPD

Institution: University of California, San Francisco
Investigator(s): George Caughey, M.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0152H Award: $545,409
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
These studies propose a functional genomics approach to the identification of new genes, functions and modes of regulation of tryptases, which are the most abundant proteins of human mast cells. They are serine proteases with trypsin-like substrate specificity and are stored in secretory granules. With heparin and histamine, they are released extracellularly after mast cell activation by antigen-bound IgE, neuropeptides and other stimuli, including cigarette smoke. Except for small amounts expressed in basophils, known tryptases are exclusive to mast cells. They are of special interest in pulmonary diseases because their concentration is higher in the lung than in other organs, their levels in bronchoalveolar lining fluid increase after cigarette smoking and in several forms of lung disease, and their properties suggest involvement in bronchoconstriction, neutrophil recruitment, lung and airway fibrosis, and destruction of lung extracellular matrix. Tryptase inhibitors reduce early and late-phase responses in sheep and guinea pig models of allergic bronchoconstriction and show efficacy in a phase II trial in humans with asthma. Surprisingly, much about the nature, number and expression of these biologically important enzymes is poorly understood.

Recent discoveries in the Principal Investigator’s laboratory reveal the existence of multiple copies of known tryptases in the human genome in distinct multigene loci, as well as the presence of previously unsuspected novel members of the tryptase gene family. The studies proposed here will 1) identify and characterize genes encoding known and novel tryptases, 2) identify mechanisms regulating levels of tryptase mRNA 3) establish cell and tissue expression of novel tryptase mRNA and protein, and 4) determine physiological and enzymological characteristics of novel tryptases as predictors of possibly novel function. These studies will clarify the basis of the exceptional levels of tryptase gene expression in humans.

Because tryptases are specific to mast cells and are their most abundant products, the study of tryptase gene regulation eventually may lead to the identification of "master" regulatory proteins controlling the expression of the mast cell's unique repertoire of proteins and mediators. In addition, the search for novel tryptases may lead to the identification of new enzymes with important functions in lung and airway biology.
Publications

Genetic deficiency of human mast cell alpha-tryptase
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Soto D, Malmsten C, Blount JL, Caughey GH ART
Yr: 2001 Vol: 163 Nbr: Abs: A232 Pg:

Genetic deficiency of human mast cell alpha-tryptase.
Periodical: Clinical and Experimental Allergy Index Medicus:
Authors: Soto D, Malmsten C, Blount JL, Muilenberg DJ, and Caughey GH ART
Yr: 2002 Vol: 32 Nbr: Abs: Pg: 1000-1006

Mast cell tryptases: New insights into genetics, activation, and function.
Periodical: Molecular Immunology Index Medicus:
Authors: Caughey GH ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Genomic organization, flanking regions and recombinant expression of mouse prostasin (prss8).
Periodical: FASEB Journal Index Medicus:
Authors: Verghese GM, and Caughey GH ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Structure and activity of human pancreasin, a novel tryptic serine peptidase expressed primarily by the pancreas.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Bhagwandin VJ, Hau L W-T, Mllen-St. Clair J, Wolters PJ, Caughey GH ART
Yr: 2003 Vol: 278 Nbr: Abs: Pg: 3363-71

New developments in the genetics and activation of mast cell proteases.
Periodical: Molecular Immunology Index Medicus:
Authors: Caughey GH ART
Yr: 2002 Vol: 38 Nbr: Abs: Pg: 1353-1357

Mast cells are activated after receptor tyrosine kinase EphB4 phosphorylation.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Soto D, Maier G, Chaudhary K, Cahghey GH ABS
Yr: 2003 Vol: 167 Nbr: Abs: Pg: A643