Vein Wall Fibrotic Injury After DVT is SLC-CCR7 Dependent

描述（由申请人提供）：深静脉血栓形成（DVT）最常见的后遗症是血栓后综合征（PTS）。这是一种严重的病态疾病，由继发于溶解性血栓的炎症反应的静脉壁损伤引起。DVT后静脉壁重塑类似于许多以慢性不可逆纤维化变化为特征的疾病。趋化因子SLC（CCL 21）及其主要受体CCR 7已被证明在人类和实验性纤维化器官损伤中是不可或缺的。结合我们的初步数据，我们认为SLC-CCR 7轴对DVT的解决和病理性静脉壁损伤反应至关重要。在这个提议中，我们测试了SLC通过CCR 7信号传导介导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。我：确定血栓形成性损伤对静脉壁SLC-CCR 7表达的作用; II：确定SLC对DVT后静脉壁细胞基质蛋白产生、增殖和蛋白酶活性的作用和机制，以及SLC对DVT后内皮向间充质转化的贡献; III：为了证明骨髓来源的CCR 7阳性细胞直接介导DVT后静脉壁纤维化损伤，并且目前可用的疗法和抗CCR 7策略可以逆转早期纤维化损伤。目前的建议将阐明SLC的作用，其效应细胞，CCR 7阳性白细胞，静脉壁重塑的几种机制的血栓性损伤的小鼠，并在体外静脉壁细胞分析。本研究的长期目标是确定DVT后静脉壁纤维化损伤的基本机制，并将其转化为人类医学治疗，以：1）加速DVT消退而无抗凝风险; 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：这个建议将建立一个趋化因子，介导循环伤口愈合细胞在深静脉血栓形成后静脉壁重塑的作用。长期目标是确定减少血栓后综合征的治疗方法，血栓后综合征是深静脉血栓形成的常见和病态并发症。

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.