Role of metalloproteinases in deep vein thrombosis

金属蛋白酶在深静脉血栓形成中的作用

• 批准号: 7407049
• 负责人: Khanh P. Nguyen
• 金额: $ 4.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407049
• 关键词: Affect; American; Biochemical Genetics; Biological Assay; Blood Clot; Blood coagulation; Cellulitis; Chronic; Condition; Deep Vein Thrombosis; Dermatitis; Development; Disease; Edema; Evolution; Foundations; Future; Gelatinase A; Gelatinase B; Gelatinases; Genes; Interstitial Collagenase; Investigation; Leg; Lower Extremity; Matrix Metalloproteinases; Metalloproteases; Metalloproteinase Gene; Morbidity - disease rate; Mus; Patients; Play; Postphlebitic Syndrome; Protein Overexpression; Proteins; Pruritus; Resolution; Role; Skin; Skin Pigmentation; Structure; Syndrome; Testing; Therapeutic; Thrombus; Tissues; Ulcer; Vascular remodeling; Veins; Week; cell motility; chronic pain; deep vein; disability; human MMP14 protein; in vivo; research study

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.

描述（由申请人提供）：深静脉血栓形成（DVT）是一种疾病，血凝块（血栓）在深静脉中发生，通常是下肢的静脉。这种疾病每年影响超过200万美国人。这些患者中约有25-75％将继续发展后毕业后疾病，与慢性残疾和发病率有关，这是最初的血栓后数周到几个月。卑鄙的综合征表现为持续的腿部水肿，慢性疼痛和急剧的皮肤变化，包括皮肤色素沉着，瘙痒，纤维炎，皮炎和溃疡。尽管尚不清楚有关DVT发育及其发展为短肢综合征的演变的机制，但初步研究已将基质金属蛋白酶（MMP）基因确定为关键参与者。 MMP在指导细胞迁​​移和组织重塑中起着至关重要的作用，并且在血栓分辨率期间诱导其表达。该建议将使用晚期遗传和生化测定法阐明MMP在体内血栓分辨率中的功能。虽然已经确定了超过23个不同的MMP，但特别是三个在血管重塑中起关键作用：两个明胶酶MMP-2和MMP-9，一个明胶激活剂MMP-14（膜型MMP MMP 1，MMP 1，MT-1-MMP）。该建议将在血栓分辨率中测试这三个特定金属蛋白酶基因MMP-2，MMP-9和MMP-14的功能。首先，我们将通过研究这些基因的靶向缺失的小鼠中的血栓分辨率来探讨MMP-2，MMP-9和MMP-14的体内需求。接下来，我们将通过过度表达这些基因来描述MMP蛋白的潜在治疗作用，从而潜在地加速了血栓分辨率。最终，这些实验将确定MMP在血栓分辨率中的体内作用，并为未来对MMP的潜在治疗应用的研究奠定了基础。