Nearly the entire weight of a mouse mast cell's (MC's) secretory granules consists of 16 neutral proteases ionically bound to serglycin proteoglycans (SGPGs) that contain either heparin (HP) or highly sulfated chondroitin (ChS) chains such as ChS-E. We and others have shown that some of these protease/SGPG complexes play beneficial roles in innate and acquired immunity. For example, mouse MC protease (mMCP)-6/HP complexes play an anti-bacterial role in the lung. However, it is now clear that some of these complexes contribute to the pathology that occurs in MC-mediated clinical disorders. For example, exocytosed mMCP-5/HP complexes cause muscle rhabdomyolysis in a hindlimb ischemia-reperfusion model of hypoxia injury. The post-translational mechanism by which only properly folded proteases are stored in the granules and the mechanism by which MCs minimize autolysis of their associated proteases are unknown. Depending on the cytokine microenvironment, mouse and human MCs synthesize different types of glycosaminoglycans (GAGs) onto serglycin. The finding that HP dramatically alters the substrate specificity of the tryptase mMCP-6 raises the possibility that ChS-E plays a similar regulatory role for other MC tryptases and/or chymases. The overall objective of Project 1 is to use complementary biochemistry, immunology, cell biology, crystallographic, and molecular biology approaches to deduce how SGPGs and their unique GAGs control the expression, granule storage, enzymatic activity, and extracellular metabolism of the different MC granule proteases.
In Specific Aim 1, we will screen our phage-display peptide libraries with recombinant MC proteases in the presence and absence of MC-derived GAGs to determine if the type of carbohydrate chain attached to a SGPG differentially alters the enzymatic activity of each investigated protease. The potential roles of SGPGs in the regulation of the extracellular metabolism of MC proteases, including their inactivation by serpins and other naturally occurring protease inhibitors will be investigated. We also will determine the crystal structure of human MC tryptase beta1 complexed to it's preferred GAG.
In Specific Aim 2, we will evaluate the ability of our HP- and mMCP-5-null mice (as well as newly created mMCP-6- and ChS-E-null mice) to combat bacteria and helminth infections. These transgenic mice also will be use to ascertain the role of MC protease/SGPG complexes in baseline and antigen-induced airway reactivity, fibrosis, and remodeling.
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