OXPAPC induction of Tissue Factor

OXPAPC 诱导组织因子

基本信息

批准号：
8089280
负责人：
Albert Phillip Owens III
金额：
$ 4.84万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089280
关键词：
Acute Americas Antibodies Antithrombins Arterial Fatty Streak Atherosclerosis Binding Blood Vessels Bone Marrow Bone Marrow Transplantation Cardiovascular Diseases Cause of Death Cells Cessation of life Coagulants Coagulation Process Communities Diet Event Fatty acid glycerol esters Female Generations Human Hyperlipidemia Lead Lipids Lipoproteins Low Density Lipoprotein Receptor Low Density Lipoprotein oxidation MM-LDL Measures Medical Modeling Mus Myelogenous Myeloid Cells Myocardial Infarction Peripheral Blood Mononuclear Cell Phenotype Phospholipids Phosphorylcholine Production Risk Role Signal Induction Source Stimulus Stroke Syndrome System Testing Therapeutic Thrombin Thromboplastin Thrombosis Time United States antithrombin III-protease complex feeding human TLR4 protein macrophage male monocyte mouse model mouse toll-like receptor 4 neutralizing antibody oxidation oxidized low density lipoprotein oxidized phosphatidyl choline receptor research study toll-like receptor 4 treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Arterial thrombosis resulting from disruption of atherosclerotic plaques is a leading cause of death due to acute thrombosis. Previous studies have demonstrated that hyperlipidemia significantly increases the risk of arterial thrombosis via activation of coagulation. Tissue factor (TF), the cellular activator of the clotting cascade, is induced when monocytes are exposed to oxidized lipoproteins. Activation of monocytes results in the subsequent release of TF-positive microparticles (MPs), which represent a source of circulating TF in hypercoagulable states. A class of minimally oxidized lipoproteins, including the phospholipid oxidation product oxPAPC, have previously been demonstrated to activate the Toll-like 4 (TLR4) receptor. We will test the hypothesis that oxidized lipoproteins are associated with activation of the coagulation system by binding to TLR4 on monocytes and inducing the expression of TF and the release of TF-positive MPs. My proposal is divided into two aims. Aim 1 will determine the mechanism by which oxPAPC induces TF expression in monocytes and the generation of TF-positive MPs. We will measure TF expression in oxPAPC treated monocytes/macrophages. We will utilize mouse monocytes/macrophages deficient in TLR4, and human monocytes with an inhibitory anti-TLR4 antibody. Aim 2 will delineate the role of monocyte-derived MP TF in the activation of coagulation in hyperlipidemic mice. The effects of TF blockade on thrombin-antithrombin (TAT), a marker of activation of coagulation, will be determined using TF neutralizing antibody in a mouse model of hyperlipidemia. Further analyses will be performed using bone marrow transplantation of either low TF or myeloid deficient Lys-M TF, into LDLr-/- mice. This will determine if reducing monocyte-derived, TF-positive MPs reduces TAT and time to occlusion in a mouse model of arterial thrombosis. These studies will increase our understanding of how lipidemia modulates levels of circulating TF and whether the major source of TF-positive MPs is monocytes. Over 80,000,000 people in the Unites States suffer from one or more forms of cardiovascular disease (CVD) and over 850,000 of these cases result in death every year, making it the number one killer in America. Plaque disruption and subsequent arterial thrombosis is a critical event in atherosclerosis resulting in acute vascular syndromes, such as myocardial infarction and stroke. Increased understanding of the mechanisms of thrombosis in CVD will enable the scientific and medical communities to make advances in therapeutics and treatment strategies.

描述（由申请人提供）：由动脉粥样硬化斑块破坏引起的动脉血栓形成是急性血栓形成导致死亡的主要原因。先前的研究表明，高脂血症通过激活凝血显着增加动脉血栓形成的风险。当单核细胞暴露于氧化脂蛋白时，组织因子 (TF) 是凝血级联的细胞激活剂。单核细胞的激活导致随后释放 TF 阳性微粒 (MP)，这是处于高凝状态的循环 TF 的来源。一类最低限度氧化的脂蛋白，包括磷脂氧化产物 oxPAPC，先前已被证明可以激活 Toll 样 4 (TLR4) 受体。我们将检验氧化脂蛋白通过与单核细胞上的 TLR4 结合并诱导 TF 表达和 TF 阳性 MP 释放而与凝血系统激活相关的假设。我的建议分为两个目标。目标 1 将确定 oxPAPC 诱导单核细胞中 TF 表达以及 TF 阳性 MP 产生的机制。我们将测量 oxPAPC 处理的单核细胞/巨噬细胞中的 TF 表达。我们将利用缺乏 TLR4 的小鼠单核细胞/巨噬细胞，以及具有抑制性抗 TLR4 抗体的人类单核细胞。目标 2 将描述单核细胞来源的 MP TF 在高脂血症小鼠凝血激活中的作用。将在高脂血症小鼠模型中使用 TF 中和抗体来确定 TF 阻断对凝血酶-抗凝血酶 (TAT)（凝血激活标志物）的影响。将使用低 TF 或骨髓缺陷 Lys-M TF 的骨髓移植到 LDLr-/- 小鼠中进行进一步分析。这将确定减少单核细胞来源的 TF 阳性 MP 是否会减少动脉血栓形成小鼠模型中的 TAT 和闭塞时间。这些研究将加深我们对血脂如何调节循环 TF 水平以及 TF 阳性 MP 的主要来源是否是单核细胞的理解。美国有超过 80,000,000 人患有一种或多种心血管疾病 (CVD)，每年有超过 850,000 例此类病例导致死亡，使其成为美国第一大杀手。斑块破坏和随后的动脉血栓形成是导致急性血管综合征（例如心肌梗塞和中风）的动脉粥样硬化的关键事件。加深对心血管疾病血栓形成机制的了解将使科学界和医学界能够在治疗方法和治疗策略方面取得进展。