Role of Lipoprotein Receptors in Venous Thrombosis

脂蛋白受体在静脉血栓形成中的作用

• 批准号: 8435382
• 负责人: Dudley K. Strickland
• 金额: $ 36.53万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435382
• 关键词: Anticoagulant therapy; Atherosclerosis; Biological Assay; Blood Vessels; Cells; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Research; Coagulation Process; Competence; Cytolysis; Data; Deep Vein Thrombosis; Development; Disease; Embolism; Endocytosis; Engineering; Event; Exhibits; Familial Hypercholesterolemia; Family member; Fibrinolysis; Gelatinase A; Genes; Genetic; Hepatic; Inflammation; Inflammatory; Inflammatory Response; LDL-Receptor Related Protein 1; Lead; Lesion; Lipoprotein Receptor; Lipoproteins; Low Density Lipoprotein Receptor; Lung; Mediating; Messenger RNA; Modeling; Mus; Outcome; Pain; Pathogenesis; Patients; Peptide Hydrolases; Plasma; Plasminogen Activator Inhibitor 1; Play; Postphlebitic Syndrome; Process; Pulmonary Embolism; Receptor Signaling; Recruitment Activity; Recurrence; Reflux; Resolution; Role; Signal Transduction; Skin; Smooth Muscle Myocytes; Swelling; Symptoms; Testing; Therapeutic Intervention; Thrombolytic Therapy; Thrombus; Time; Ulcer; Urokinase; Veins; Venous Thrombosis; design; experience; inhibitor/antagonist; macrophage; mouse model; neutrophil; prevent; receptor; receptor function; uptake

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.

描述(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DVT血栓消退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，在炎症反应中，中性粒细胞和巨噬细胞被招募到血栓中，并且需要蛋白酶来降解基质和血栓。我们使用DVT小鼠模型的初步数据显示，LDLR的基因缺失导致DVT小鼠模型的血栓分辨率提高。这似乎是由于LDLR缺陷小鼠的早期巨噬细胞募集到病变中所致。伴随而来的是MMP2的表达增加，这是一种与血栓溶解有关的蛋白酶，而从LDLR缺陷小鼠分离的血栓中PAI-1的表达减少。此外，我们还发现，在巨噬细胞中选择性缺失LRP1基因的小鼠，在深静脉血栓形成模型中也表现出血栓分辨率的增强。这一应用的中心假设是，在深静脉血栓形成(DVT)的小鼠模型中，某些低密度脂蛋白受体家族成员在调节炎症事件和蛋白酶活性从而调节血栓溶解方面发挥重要作用。需要检验的具体假设是：1)LDLR通过调节炎症反应来调节DVT期间的血栓溶解；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溶解；3)我们可以设计出受体阻断的抑制分子，从而提高DVT中的血栓溶解能力。这些假说将被用于下列特定目的的验证：1)确定LDLR调节DVT小鼠模型中血栓溶解的机制；2)确定LRP1在巨噬细胞中表达调控DVT小鼠模型中血栓溶解的机制；3)通过设计LDLR和LRP1的拮抗剂来开发受体阻断的策略，以提高DVT中的血栓溶解。