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，也可能导致潜在致命的肺栓塞。临床研究表明，血栓溶解是血栓形成后综合征发病机制的核心。导致深静脉血栓溶解的机制目前还不清楚。然而，很明显，血栓的最佳溶解需要炎症反应，其中中性粒细胞和巨噬细胞被募集到血栓上，并且需要蛋白酶来降解基质和血栓。我们使用小鼠DVT模型的初步数据显示，LDLr的基因缺失导致小鼠DVT模型中的血栓溶解增强。这似乎是由于巨噬细胞早期募集到ldlr缺陷小鼠的病变。同时伴有MMP2表达增加；一种蛋白酶，与从ldlr缺陷小鼠分离的血栓溶解和PAI-1表达降低有关。此外，我们发现在巨噬细胞中选择性删除LRP1基因的小鼠在深静脉血栓形成模型中也表现出增强的血栓溶解。本应用的中心假设是，某些LDL受体家族成员在调节炎症事件和蛋白酶活性中发挥重要作用，从而调节小鼠深静脉血栓（DVT）模型中的凝块溶解。需要验证的具体假设有：1)LDLr通过调节炎症调节深静脉血栓溶解；2) LRP1通过调节蛋白酶水平和调节炎症中的信号事件来调节血栓的溶解，3)我们可以设计受体阻断抑制剂分子，从而增强血栓的溶解。这些假设将在以下具体目标中得到验证：1)确定LDLr调节小鼠DVT模型中血栓溶解的机制；2)明确巨噬细胞中表达的LRP1调节小鼠DVT血栓溶解的机制；3)通过设计LDLR和LRP1拮抗剂来制定受体阻断策略，以增强DVT血栓溶解。

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.