Role of metalloproteinases in deep vein thrombosis

描述(申请人提供)：深静脉血栓形成(DVT)是一种深静脉血栓(血栓)在深静脉中形成的疾病，通常是下肢静脉。这种疾病每年影响200多万美国人；其中大约25%-75%的患者会在最初的血栓形成几周到几个月后，继续发展为与慢性残疾和发病率相关的静脉炎后综合征。白癜风后综合征表现为持续的腿部浮肿、慢性疼痛和皮肤的剧烈变化，包括皮肤色素沉着、瘙痒炎、蜂窝织炎、皮炎和溃疡。尽管调控DVT发生和演变为静脉炎后综合征的机制尚不清楚，但初步研究已确定基质金属蛋白酶(MMPs)基因是关键因素。MMPs在指导细胞迁移和组织重塑中起重要作用，其表达是在血栓溶解过程中诱导的。这项建议将利用先进的遗传和生化分析来阐明MMPs在体内血栓溶解中的作用。目前已鉴定出超过23种不同的MMPs，其中有三种似乎在血管重塑中起关键作用：两种明胶酶，即MMP2和MMP9，以及一种明胶酶激活剂MMP14(膜型MMP1，MT-1-MMPs)。这项建议将测试这三个特定的金属蛋白酶基因，基质金属蛋白酶-2，基质金属蛋白酶-9，和基质金属蛋白酶-14，在血栓溶解中的功能。首先，我们将通过研究靶向缺失这些基因的小鼠血栓溶解来探索体内对基质金属蛋白酶-2、基质金属蛋白酶-9和基质金属蛋白酶-14的需求。接下来，我们将通过过量表达这些基因来描述基质金属蛋白酶蛋白在血栓中的潜在治疗作用，以潜在地加速血栓的溶解。最终，这些实验将确定MMPs在体内对血栓的溶解作用，并为未来MMPs潜在的治疗应用研究提供基础。

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.