Vein Wall Fibrotic Injury After DVT is SLC-CCR7 Dependent

描述(申请人提供)：深静脉血栓形成(DVT)最常见的后遗症是血栓形成后综合征(PTS)。这是一种严重的病态疾病，由静脉壁损伤引起，继发于溶解血栓的炎症反应。DVT后静脉壁重塑类似于许多以慢性不可逆转的纤维化改变为特征的疾病。趋化因子SLC(CCL21)及其主要受体CCR7在人和实验性纤维化器官损伤中都是不可或缺的。结合我们的初步数据，我们认为SLC-CCR7轴对DVT的分辨率和病理性静脉壁损伤反应至关重要。在这项建议中，我们检验了SLC通过CCR7信号介导DVT后静脉壁纤维化损伤的总体假设。这将通过三个具体目标来解决。一：明确血栓形成损伤对静脉壁SLC-CCR7表达的影响；二：确定SLC对DVT后静脉壁细胞基质蛋白的产生、增殖和蛋白酶活性的影响及其机制，以及SLC在DVT后血管内皮细胞间质转化中的作用；三：证实骨髓来源的CCR7阳性细胞直接介导DVT后静脉壁纤维化损伤，现有治疗方法和抗CCR7策略可以逆转早期纤维化损伤。目前的建议将阐明SLC及其效应细胞CCR7阳性白细胞通过几种血栓性损伤机制和体外静脉壁细胞分析在静脉壁重建中的作用。这项研究的长期目标是明确DVT后静脉壁纤维化损伤的基本机制，并将其转化为人类药物治疗：1)在没有抗凝风险的情况下加速DVT的消退：2)减少静脉壁纤维化损伤，从而降低PTS的发生率。 公共卫生相关性：这项提案将确定一种趋化因子在深静脉血栓形成后静脉壁重塑中的作用，该趋化因子介导循环伤口愈合细胞。长期目标是确定一种治疗方法，以减少血栓形成后综合征，血栓后综合征是深静脉血栓形成的常见和病理性并发症。

DESCRIPTION (provided by applicant): The most common sequela of deep vein thrombosis (DVT) is post thrombotic syndrome (PTS). This is a significantly morbid disease that results from vein wall injury secondary to the inflammatory response of the lysing thrombus. Post DVT vein wall remodeling resembles many diseases that are characterized by chronic irreversible fibrotic changes. The chemokine SLC (CCL21) and its primary receptor, CCR7, have been shown to be integral in both human and experimental fibrotic organ injury. In conjunction with our preliminary data, we believe the SLC-CCR7 axis is critical to DVT resolution and pathological vein wall injury response. In this proposal we test the overall hypothesis that SLC, via CCR7 signaling, mediates vein wall fibrotic injury after DVT. This will be addressed by three Specific Aims. I: To define the role of thrombogenic injury on vein wall SLC-CCR7 expression; II: To determine the effect and mechanism of SLC on post-DVT vein wall cellular matrix protein production, proliferation, and proteinase activity, and the contribution of SLC to endothelial to mesenchymal transformation after DVT; III: To demonstrate that bone marrow derived CCR7 positive cells directly mediate vein wall fibrotic injury after DVT, and that currently available therapies and anti- CCR7 strategies can reverse early fibrotic injury. The current proposal will elucidate the role of SLC, and its effector cell, the CCR7 positive leukocyte, on vein wall remodeling by several mechanisms of thrombotic injury in the mouse, and by in vitro vein wall cellular analysis. The long-term goal of this study is to define the basic mechanisms of post DVT vein wall fibrotic injury with the translation to human medical therapies to: 1) accelerate DVT resolution without anticoagulation risks: 2) to reduce vein wall fibrotic injury and thus reduce the incidence of PTS. PUBLIC HEALTH RELEVANCE: This proposal will establish the role of a chemokine that mediates a circulating wound healing cell in vein wall remodeling after deep vein thrombosis. The long term goal is to define a therapy to decrease post thrombotic syndrome, a common and morbid complication of deep vein thrombosis.