Study and selective targeting of monomeric and trimeric gelatinase B/ MMP-9

Neutrophils are the recce troops of the innate immune system. Upon neutrophil activation, vesicles transport cell adhesion molecules and proteases to the cell surface. Adhesion molecules assist in rolling, adhesion, crawling and transmigration while proteases, such as matrix metalloproteinase-9 (MMP-9), assist in migration of neutrophils through basement membranes and extracellular matrix. Once at the site of inflammation, proteases modulate immune signals and help clear pathogens. Neutrophil-derived MMP-9, characterized as being devoid of tissue inhibitor of matrix metalloprotease-1 (TIMP-1), induces the formation of new blood vessels at sites of non-sterile or sterile inflammation. MMP-9 is secreted as monomers, heterocomplexes and homotrimers. Recently, we discovered that homotrimeric MMP-9 has different characteristics with importance in neutrophil-mediated physiological (e.g. wound healing) and pathological processes (e.g. rheumatoid arthritis). In this proposal, we want to expand knowledge on the biochemistry and biology of MMP-9 forms in two ways; we will test inhibitory molecules that discriminate between monomeric and trimeric MMP-9 and use these inhibitors as selective tools to track separate MMP-9 forms.