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）。这是一种明显的病态疾病，由静脉壁损伤继发于溶栓的炎症反应。深静脉血栓栓塞后的静脉壁重塑类似于许多以慢性不可逆纤维化改变为特征的疾病。趋化因子SLC （CCL21）及其主要受体CCR7已被证明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的消退和病理性静脉壁损伤反应至关重要。在本提案中，我们验证了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。1：明确血栓性损伤对静脉壁SLC-CCR7表达的影响；II：确定SLC对DVT后静脉壁细胞基质蛋白生成、增殖、蛋白酶活性的影响及机制，以及SLC对DVT后内皮细胞向间质细胞转化的贡献；III：证明骨髓源性CCR7阳性细胞直接介导DVT后静脉壁纤维化损伤，现有的治疗方法和抗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阳性白细胞在小鼠血栓性损伤的几种机制中对静脉壁重塑的作用，并通过体外静脉壁细胞分析。本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，并将其转化为人类医学治疗，以：1)加速DVT的消退，而不存在抗凝风险；2)减少静脉壁纤维化损伤，从而降低PTS的发生率。

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.