Role of Lipoprotein Receptors in Venous Thrombosis

描述（由申请人提供）：深静脉血栓形成（DVT）是一个重要的临床问题，也可能导致潜在的致命性肺栓塞。临床研究表明，血栓消退是血栓后综合征发病机制的核心.导致DVT中血栓消退的机制目前还不清楚。然而，很明显，血栓的最佳消退需要炎症反应，其中中性粒细胞和巨噬细胞被募集到血栓中，并且需要蛋白酶来降解基质和血栓。我们采用DVT小鼠模型的初步数据显示，LDLr基因缺失导致DVT小鼠模型中血栓消退增强。这似乎是由于LDL r缺陷小鼠中巨噬细胞早期募集到病变中所致。这伴随着MMP 2表达的增加;在从LDL r缺陷小鼠分离的血栓中，MMP 2是一种与血栓消退有关的蛋白酶，派-1表达减少。此外，我们发现，在巨噬细胞中选择性删除LRP 1基因的小鼠在深静脉血栓形成模型中也表现出血栓消退增强。本申请的中心假设是某些LDL受体家族成员在调节炎症事件和蛋白酶活性中起重要作用，从而调节深静脉血栓形成（DVT）小鼠模型中的凝块消退。待检验的具体假设是：1）LDLr通过调节炎症来调节DVT期间的血栓消退; 2）LRP 1通过调节蛋白酶水平和调节炎症中的信号传导事件来调节血栓消退; 3）我们可以设计受体阻断抑制剂分子，以增强DVT中的血栓消退。将在以下特定目的中检验这些假设：1）确定LDLr调节DVT小鼠模型中血栓消退的机制; 2）确定巨噬细胞中表达的LRP 1调节DVT小鼠模型中血栓消退的机制; 3）通过设计LDLR和LRP 1拮抗剂来开发受体阻断策略，以增强DVT中的血栓消退。

DESCRIPTION (provided by applicant): Deep venous thrombosis (DVT) is a significant clinical problem that can also lead to potentially fatal pulmonary embolism. Clinical studies reveal that thrombus resolution is central to the pathogenesis of post- thrombotic syndrome. Mechanisms that lead to thrombus resolution in DVT are not well understood at this time. It is clear, however, that optimal resolution of the thrombus requires an inflammatory response in which neutrophil and macrophages are recruited to the thrombus, and require proteases to degrade the matrix and thrombus. Our preliminary data employing mouse models of DVT reveal that genetic deletion of the LDLr results in enhanced thrombus resolution in mouse models of DVT. This appears to result from early recruitment of macrophages into the lesion in LDLr-deficient mice. This is accompanied by increased expression of MMP2; a protease implicated in thrombus resolution and decreased expression of PAI-1 in the thrombus isolated from LDLr-deficient mice. Further, we discovered that mice in which the LRP1 gene has been selectively deleted in macrophages also demonstrate enhanced thrombus resolution in a model of deep vein thrombosis. The central hypothesis of this application is that certain LDL receptor family members play important roles in modulating inflammatory events and protease activity thereby regulating clot resolution in mouse models of Deep Vein Thrombosis (DVT). The specific hypotheses to be tested are: 1) that the LDLr modulates thrombus resolution during DVT by modulating inflammation; 2) that LRP1 modulate thrombus resolution by regulating protease levels and by regulating signaling events in inflammation and 3) that we can engineer inhibitor molecules for receptor blockade that would enhance thrombus resolution in DVT. These hypotheses will be tested in the following specific aims: 1) Determine mechanisms by which the LDLr regulates thrombus resolution in mouse models of DVT; 2) Define the mechanisms by which LRP1 expressed in macrophages modulates thrombus resolution in mouse models of DVT and 3) Develop strategies for receptor blockade by designing antagonists for LDLR and LRP1 to enhance thrombus resolution in DVT.