OXPAPC induction of Tissue Factor

OXPAPC 诱导组织因子

• 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
• 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

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）：动脉粥样硬化斑块引起的动脉血栓形成是由于急性血栓形成引起的死亡原因。先前的研究表明，高脂血症通过激活凝血而显着增加了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）是凝结级联反应的细胞活化剂。单核细胞的激活导致随后释放TF阳性微粒（MPS），该微粒代表了高凝状态下循环TF的来源。先前已证明一类最小氧化的脂蛋白，包括磷脂氧化产物OXPAPC，可以激活类似Toll样的4（TLR4）受体。我们将检验以下假设：氧化的脂蛋白通过与单核细胞上的TLR4结合并诱导TF的表达和TF阳性MP的释放，与凝结系统的激活相关。我的建议分为两个目标。 AIM 1将确定OXPAPC在单核细胞中诱导TF表达和TF阳性MP的产生的机制。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抗体的人单核细胞。 AIM 2将描绘单核细胞衍生的MP TF在高脂血症小鼠中凝血激活中的作用。 TF阻滞对凝血激活标记凝血酶 - 抗凝结蛋白（TAT）的影响将使用TF中和抗体在小鼠高脂血症模型中确定。将使用低TF或髓样不足的Lys-M TF的骨髓移植进行进一步的分析，并将其纳入LDLR - / - 小鼠中。这将确定减少单核细胞衍生的TF阳性MPS是否会减少TAT和时间在小鼠动脉血栓形成模型中的时间。这些研究将增加我们对脂质血症如何调节循环TF水平以及TF阳性MPS的主要来源是否是单核细胞的理解。在团结州，超过80,000,000人患有一种或多种形式的心血管疾病（CVD），其中85万人每年都会导致死亡，使其成为美国第一杀手。斑块破坏和随后的动脉血栓形成是动脉粥样硬化的关键事件，导致急性血管综合征（例如心肌梗塞和中风）。对CVD中血栓形成机制的理解增加将使科学和医学界能够在治疗和治疗策略方面取得进步。