My lab explores roles of mast cells and peptidases in bronchi and lung. Focusing on peptidases released by mast cells, we characterized their major secreted proteins: the tryptases and chymases. Achievements include the first cloning of a tryptase and human chymases and discovery of new functions of these enzymes as peptidases, secretagogues, mitogens and modulators of airway smooth muscle tone. We identified tryptase and chymase inhibitors and helped launch pharmaceutical development of tryptase inhibitors for asthma. We discovered new tryptases and identified important polymorphisms and human deficiency states. Our studies of chymases involve crystallization, modeling and establishment of structure-activity relationships, particularly relating to cleavage of angiotensin I to generate vasoactive angiotensin II. We are characterizing mouse models of selective protease and mast cell deficiency, identifying roles for mast cell products in protection from airway infection and sepsis. Our recent work with experimental models suggests ways in which mast cells influence tissue remodeling, scarring, tumor progression, and innate immune responses, which differ from the acute allergic phenomena with which mast cells are traditionally linked. These studies are helping to redefine the mast cells' role in biology. Our work with mast cell proteases has led us to explore phylogenetically related groups of exotic mammalian peptidases that form extracellular proteasome-like structures or are anchored to the surface of cell membranes. Our studies suggest that one of these, PRSS8/prostasin, is expressed on the luminal surface of lung and kidney epithelium, where it regulates sodium transport, which is critical for maintaining proper hydration of airway secretions and for regulating blood volume. We are exploring prostasin's contribution to the excessive drying of airway secretions in cystic fibrosis and its potential as target for therapeutic inhibition. |
Biomedical Sciences (BMS) Graduate Program
