Fibrotic effects and regulation of MMP proteins in thrombus resolution

深静脉血栓形成（DVT）每年影响超过200万美国人。静脉炎后综合征 可影响25-75%的DVT患者，包括腿部肿胀、疼痛、皮肤变化和溃疡。 皮肤这仅发生在DVT患者的一个子集中，表明血栓消退在DVT患者中至关重要。 确定慢性静脉阻塞和纤维化是否会发展并导致静脉炎后 综合征基质金属蛋白酶（MMP）基因对细胞迁移和组织重塑至关重要， 在血栓消退过程中表达和激活，表明在该过程中起关键作用。农村妇女在消除 静脉炎后综合征的发病机制将被定义为三个特定的目的：1）定义静脉炎后综合征的发病机制， MMP-2基因的区域和对血栓诱导的MMP-2至关重要的同源转录因子 MMP-2、MMP-9和MMP-14（MT-MMP-f）在DVT消退中的作用， 3）检测血栓诱导的静脉壁纤维化中MMP蛋白（MMP-2、MMP-9）的过度表达， 和MMP-14）加速DVT消退并改变血栓诱导的静脉壁纤维化。一系列独特的 将使用转基因MMP-2报告小鼠来确定MMP-2基因的哪些区域是必需的 血栓诱导的MMP-2转录和染色质免疫沉淀将用于鉴定 同源转录因子。将使用具有各种MMP基因的靶向缺失的小鼠来确定 这些酶在血栓再通、静脉壁纤维化和静脉壁顺应性丧失中的作用， 使用小鼠静脉生物力学的新测定来研究弹性。 MMP-2、MMP-14和MMP-9以及编码这些同种型的腺病毒载体将用于过表达 这些蛋白质在血栓消退过程中，以确定DVT的消退是否加速， 这些研究将确定MMP蛋白在血管壁生物力学中的作用， 血栓溶解的有害方面，并表征潜在的分子治疗，以防止后 静脉炎综合征 相关性：该提案将确定基质金属蛋白酶蛋白如何引起瘢痕形成， 血栓形成后静脉增厚，这可能会导致以后的腿部疼痛，肿胀和溃疡。这些研究将 增加静脉如何被血栓破坏的知识，并测试新的治疗方法来防止这种损害。

Deep venous thrombosis (DVT) affects more than 2 million Americans per year. Post-phlebitic syndrome can affect 25-75% of patients following DVT and includes leg swelling, pain, skin changes and ulceration of the skin. This develops only in a subset of DVT patients, suggesting that thrombus resolution is critical in determining whether chronic venous obstruction and fibrosis will develop and lead to post-phlebitic syndrome. Matrix metalloproteinase (MMP) genes, critical to cell migration and tissue remodeling, are expressed and activated during thrombus resolution suggesting a critical role in this process. Their role in the pathogenesis of post-phlebitic syndrome will be defined with three Specific Aims: 1) To define the regions of the MMP-2 gene and cognate transcription factors critical to thrombus-induced MMP-2 expression, 2) To determine the role of MMP-2, MMP-9 and MMP-14 (MT-MMP-f) in DVT resolution and thrombus-induced vein wall fibrosis, 3) To determine if overexpression of MMP proteins (MMP-2, MMP-9 and MMP-14) accelerates DVT resolution and alters thrombus-induced vein wall fibrosis. A unique series of transgenic MMP-2 reporter mice will be used to determine which regions of the MMP-2 gene are essential for thrombus-induced MMP-2 transcription and chromatin immunoprecipitation will be used to identity the cognate transcription factors. Mice with targeted deletion of various MMP genes will be used to determine the role of these enzymes in thrombus recanalization, vein wall fibrosis and loss of vein wall compliance and elasticity using novel assays of mouse vein biomechanics.Tissue-specific transgenic overexpression of MMP-2, -14 and -9 as well as adenoviral vectors encoding these isoforms will be utilized to overexpress these proteins during thrombus resolution to determine resolution of DVT is accelerated and the effects on fibrosis and vein wall biomechanics.These studies will define the role of MMP proteins in the beneficial and detrimental aspects of thrombus resolution, and characterize potential molecular therapy to prevent post- phlebitic syndrome. RELEVANCE: This proposalwill determine how matrix metalloproteinase proteins cause scarring and thickening of veins after blood clots, which can cause later leg pain, swelling and ulcers. These studies will increase knowledge of how veins are damaged by clots and test new treatments to prevent this damage.