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: 8320618
• 负责人: Dudley K. Strickland
• 金额: $ 38.38万
• 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/8320618
• 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. PUBLIC HEALTH RELEVANCE: Deep vein thrombosis (DVT) and resulting pulmonary embolism represents a significant clinical problem. Clinical studies reveal that rapid resolution o the thrombus is a critical factor for patient outcomes. Those patients whose thrombus resolves slowly often experience damage to the veins. We have discovered two new molecules, the LDL receptor and LRP1 that modulate thrombus resolution in mouse models. These studies will identify new mechanisms that modulate this process, and will allow us to develop new strategies for potential therapeutic intervention in this disease.

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肺栓塞。临床研究表明，血栓分辨率对于血栓形成综合征的发病机理至关重要。目前尚不清楚导致DVT中血栓分辨率的机制。但是，很明显，血栓的最佳分辨率需要炎症反应，其中嗜中性粒细胞和巨噬细胞被募集到血栓上，并需要蛋白酶以降解基质和血栓。我们采用DVT小鼠模型的初步数据表明，LDLR的遗传缺失导致DVT小鼠模型中的血栓分辨率增强。这似乎是由于巨噬细胞早期募集到LDLR缺陷小鼠病变中而引起的。这伴随着MMP2的表达增加。与从LDLR缺陷型小鼠分离的血栓中的血栓分辨率和PAI-1表达降低的蛋白酶。此外，我们发现在巨噬细胞中选择性删除LRP1基因的小鼠也表明了深静脉血​​栓形成模型中的血栓分辨率增强。该应用的核心假设是某些LDL受体家族成员在调节炎症事件和蛋白酶活性中起着重要作用，从而调节了深静脉血​​栓形成小鼠模型（DVT）的凝块分辨率。要测试的特定假设是：1）LDLR通过调节炎症在DVT期间调节血栓分辨率； 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分辨率，3）我们可以为受体阻断设计抑制剂分子，以提高DVT中的血栓分辨率。这些假设将在以下特定目的中进行测试：1）确定LDLR调节DVT小鼠模型中血栓分辨率的机制； 2）定义LRP1在巨噬细胞中表达的机制调节DVT小鼠模型中的血栓分辨率和3）通过设计LDLR和LRP1的拮抗剂来增强DVT中的血栓分辨率来制定受体阻断的策略。 公共卫生相关性：深静脉血栓形成（DVT）和由此产生的肺栓塞是一个重大的临床问题。临床研究表明，快速分辨率o血栓是患者结局的关键因素。那些血栓缓慢解决的患者经常会对静脉造成损害。我们发现了两个新分子，即LDL受体和LRP1，它们在小鼠模型中调节血栓分辨率。这些研究将确定调节这一过程的新机制，并使我们能够制定新的策略来对该疾病进行潜在的治疗干预。