Role of metalloproteinases in deep vein thrombosis

描述（由申请人提供）：深静脉血栓形成（DVT）是一种在深静脉（通常是下肢静脉）中形成血块（血栓）的疾病。这种疾病每年影响超过200万美国人;这些患者中约25-75%将在初始血栓后数周至数月继续发展静脉炎后综合征，与慢性残疾和发病率相关。肺炎后综合征表现为持续性腿部水肿、慢性疼痛和剧烈的皮肤变化，包括皮肤色素沉着、皮炎、蜂窝织炎、皮炎和溃疡。虽然深静脉血栓形成及其演变为静脉炎后综合征的机制还不清楚，但初步研究已确定基质金属蛋白酶（MMP）基因是关键因素。MMPs在指导细胞迁移和组织重塑中起关键作用，并且它们的表达在血栓消退期间被诱导。该建议将阐明MMPs的功能，在血栓决议在体内使用先进的遗传和生化检测。虽然已经鉴定了超过23种不同的MMP，但三种似乎特别在血管重塑中起关键作用：两种明胶酶MMP-2和MMP-9，以及明胶酶激活剂MMP-14（膜型MMP 1，MT-1-MMP）.本研究将检测这三种特异性金属蛋白酶基因MMP-2、MMP-9和MMP-14在血栓消退中的功能。首先，我们将探索MMP-2，MMP-9和MMP-14的体内需求，通过研究这些基因中的每一个的靶向缺失的小鼠中的血栓消退。接下来，我们将通过这些基因的过度表达来描述MMP蛋白的潜在治疗作用，从而潜在地加速血栓的消退。最终，这些实验将建立在血栓决议中的MMPs在体内的作用，并为MMPs的潜在治疗应用的未来研究提供了基础。

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.