OXPAPC induction of Tissue Factor
OXPAPC 诱导组织因子
基本信息
- 批准号:7806935
- 负责人:
- 金额:$ 4.56万
- 依托单位:
- 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:
- 关键词:AcuteAmericasAntibodiesAntithrombinsArterial Fatty StreakAtherosclerosisBindingBlood VesselsBone MarrowBone Marrow TransplantationCardiovascular DiseasesCause of DeathCellsCessation of lifeCoagulantsCoagulation ProcessCommunitiesDietEventFatty acid glycerol estersFemaleGenerationsHumanHyperlipidemiaLeadLipidsLipoproteinsLow Density Lipoprotein ReceptorLow Density Lipoprotein oxidationMM-LDLMeasuresMedicalModelingMusMyelogenousMyeloid CellsMyocardial InfarctionPeripheral Blood Mononuclear CellPhenotypePhospholipidsPhosphorylcholineProductionRiskRoleSignal InductionSourceStimulusStrokeSyndromeSystemTestingTherapeuticThrombinThromboplastinThrombosisTimeUnited Statesantithrombin III-protease complexfeedinghuman TLR4 proteinmacrophagemalemonocytemouse modelmouse toll-like receptor 4neutralizing antibodyoxidationoxidized low density lipoproteinoxidized phosphatidyl cholinereceptorresearch studytoll-like receptor 4treatment 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):动脉粥样硬化斑块破裂导致的动脉血栓形成是急性血栓形成导致死亡的主要原因。以往的研究表明,高脂血症通过激活凝血功能显著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,凝血级联反应的细胞激活剂组织因子(TF)被诱导。单核细胞的活化导致TF阳性微粒(MP)的随后释放,其代表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,先前已被证明激活Toll样4(TLR 4)受体。我们将测试的假设,即氧化脂蛋白与凝血系统的激活,结合单核细胞上的TLR 4和诱导TF的表达和TF阳性MP的释放。我的建议分为两个目标。目的1探讨oxPAPC诱导单核细胞TF表达和产生TF阳性MP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TLR 4缺陷的小鼠单核细胞/巨噬细胞和具有抑制性抗TLR 4抗体的人单核细胞。目的2探讨单核细胞源性MPTF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中和抗体测定TF阻断对凝血酶-抗凝血酶(达特)(凝血激活的标志物)的影响。将使用低TF或骨髓缺陷型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衍生的TF阳性MP是否减少动脉血栓形成小鼠模型中的达特和闭塞时间。这些研究将增加我们的理解,如何调节循环TF的水平,以及TF阳性MP的主要来源是否是单核细胞。美国有超过80,000,000人患有一种或多种形式的心血管疾病(CVD),每年有超过850,000例此类病例导致死亡,使其成为美国的头号杀手。斑块破裂和随后的动脉血栓形成是导致急性血管综合征(如心肌梗死和中风)的动脉粥样硬化的关键事件。对CVD血栓形成机制的进一步了解将使科学和医学界能够在治疗和治疗策略方面取得进展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Albert Phillip Owens III其他文献
Albert Phillip Owens III的其他文献
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{{ truncateString('Albert Phillip Owens III', 18)}}的其他基金
A Vevo 3100 Small Animal Ultrasound Machine for the University of Cincinnati
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10418086 - 财政年份:2022
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Role of the Gut Microbiota in Abdominal Aortic Aneurysm
肠道微生物群在腹主动脉瘤中的作用
- 批准号:
10417110 - 财政年份:2020
- 资助金额:
$ 4.56万 - 项目类别:
Role of the Gut Microbiota in Abdominal Aortic Aneurysm
肠道微生物群在腹主动脉瘤中的作用
- 批准号:
10599215 - 财政年份:2020
- 资助金额:
$ 4.56万 - 项目类别:
Role of the Gut Microbiota in Abdominal Aortic Aneurysm
肠道微生物群在腹主动脉瘤中的作用
- 批准号:
10176258 - 财政年份:2020
- 资助金额:
$ 4.56万 - 项目类别:
The role of protease-activated receptor 2 in atherosclerosis
蛋白酶激活受体2在动脉粥样硬化中的作用
- 批准号:
10363645 - 财政年份:2018
- 资助金额:
$ 4.56万 - 项目类别:
The role of protease-activated receptor 2 in atherosclerosis
蛋白酶激活受体2在动脉粥样硬化中的作用
- 批准号:
9895849 - 财政年份:2018
- 资助金额:
$ 4.56万 - 项目类别:
Tissue Factor & Clot Formation In Abdominal Aortic Aneurysm
组织因子
- 批准号:
8637108 - 财政年份:2013
- 资助金额:
$ 4.56万 - 项目类别:
Tissue Factor & Clot Formation In Abdominal Aortic Aneurysm
组织因子
- 批准号:
8425696 - 财政年份:2013
- 资助金额:
$ 4.56万 - 项目类别:
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