Role of metalloproteinases in deep vein thrombosis

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DESCRIPTION (provided by applicant): Deep vein thrombosis (DVT) is a disease condition where blood clots (thrombi) develop in deep veins, often veins of the lower extremities. This disease affects more than 2 million Americans annually; approximately 25-75% of these patients will go on to develop post-phlebitic syndrome, associated with chronic disability and morbidity, weeks to months after the initial thrombus. Post-phebitic syndrome manifests as persistent leg edema, chronic pain, and dramatic skin changes including skin pigmentation, pruritis, cellulitis, dermatitis, and ulceration. Although the mechanisms governing DVT development and its evolution to post-phlebitic syndrome are not well understood, initial investigations have identified matrix metalloproteinase (MMP) genes as key players. MMPs play crucial roles in directing cell migration and tissue remodeling and their expression is induced during thrombus resolution. This proposal will elucidate the function of MMPs in thrombus resolution in vivo using advanced genetic and biochemical assays. While over 23 different MMPs have been identified, three in particular seem to play critical roles in vascular remodeling: two gelatinases, MMP-2 and MMP-9, and a gelatinase activator, MMP-14 (membrane- type MMP 1, MT-1-MMP). This proposal will test the functions of these three specific metalloproteinase genes, MMP-2, MMP-9, and MMP-14, in thrombus resolution. First we will explore the in vivo requirement of MMP-2, MMP-9, and MMP-14 by studying thrombus resolution in mice with targeted deletion of each of these genes. Next, we will delineate the potential therapeutic roles of MMP proteins in by overexpression of these genes to potentially accelerate thrombus resolution. Ultimately, these experiments will establish the in vivo role of MMPs in thrombus resolution and provide a foundation for future studies of potential therapeutic applications of MMPs.