12-lipoxygenase regulation of FcgRIIa-mediated platelet activation

12-脂氧合酶对 FcgRIIa 介导的血小板活化的调节

• 批准号: 9132041
• 负责人: Jennifer Yeung
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132041
• 关键词: Accounting; Adhesions; Antigen-Antibody Complex; Arachidonate 12-Lipoxygenase; Binding Proteins; Biochemical; Bleeding time procedure; Blood Platelets; Blood Vessels; Blood coagulation; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Injuries; Cause of Death; Cessation of life; Clinical; Coagulation Process; Collaborations; Complex; Cytoplasmic Granules; Cytoplasmic Tail; Data Aggregation; Disease; Enzymes; Event; Health Care Costs; Hematology; Hemorrhage; Hemostatic function; Heparin; Hydroxyeicosatetraenoic Acids; ITAM; Immune; Immunologic Receptors; Incidence; Infusion procedures; Injury; Integrins; LOX gene; Lead; Life; Lipoxygenase Inhibitors; Mediating; Medicine; Modeling; Monitor; Morbidity - disease rate; Mus; Myocardial Infarction; Nonesterified Fatty Acids; PLCgamma2; Pathway interactions; Patients; Pharmacology; Phosphorylation; Platelet Activation; Platelet Count measurement; Play; Prevention; Regulation; Risk; Role; Sepsis; Signal Pathway; Signal Transduction; Stroke; Tail; Thrombin; Thrombocytopenia; Thrombosis; Time; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Veins; design; experience; genetic approach; in vivo; inhibitor/antagonist; insight; mortality; mouse model; novel therapeutic intervention; novel therapeutics; oxidized lipid; prevent; protein complex; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; therapeutic target; Accounting; Adhesions; Antigen-Antibody Complex; Arachidonate 12-Lipoxygenase; Binding Proteins; Biochemical; Bleeding time procedure; Blood Platelets; Blood Vessels; Blood coagulation; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Injuries; Cause of Death; Cessation of life; Clinical; Coagulation Process; Collaborations; Complex; Cytoplasmic Granules; Cytoplasmic Tail; Data Aggregation; Disease; Enzymes; Event; Health Care Costs; Hematology; Hemorrhage; Hemostatic function; Heparin; Hydroxyeicosatetraenoic Acids; ITAM; Immune; Immunologic Receptors; Incidence; Infusion procedures; Injury; Integrins; LOX gene; Lead; Life; Lipoxygenase Inhibitors; Mediating; Medicine; Modeling; Monitor; Morbidity - disease rate; Mus; Myocardial Infarction; Nonesterified Fatty Acids; PLCgamma2; Pathway interactions; Patients; Pharmacology; Phosphorylation; Platelet Activation; Platelet Count measurement; Play; Prevention; Regulation; Risk; Role; Sepsis; Signal Pathway; Signal Transduction; Stroke; Tail; Thrombin; Thrombocytopenia; Thrombosis; Time; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Veins; design; experience; genetic approach; in vivo; inhibitor/antagonist; insight; mortality; mouse model; novel therapeutic intervention; novel therapeutics; oxidized lipid; prevent; protein complex; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; therapeutic target

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in the US annually, accounting for nearly 1 in 3 deaths and over $500 billion in annual health care cost in the US. Platelet-mediated thrombosis is the primary underlying mechanism leading to cardiovascular life-threatening clinical events, such as stroke or myocardial infarction One form of platelet-mediated thrombosis is through the immune-complex activation of FcγRIIa (a transmembrane receptor containing ITAM in the cytoplasmic tail). The activation of FcγRIIa is responsible for immune-mediated thrombocytopenia and thrombosis, which can often lead to life-threatening cardiovascular related complications in patients who receive heparin or experience sepsis. Platelet 12-lipoxygenase (12-LOX) has been demonstrated to be an essential modulator of FcγRIIa-mediated platelet activation; however, the underlying signaling mechanism by which 12-LOX regulates the FcγRIIa signaling is still unclear. Understanding the signaling mechanisms by which 12-LOX regulates this pathway is a critical step in validating its role as a potential and effective anti-platelet target for the prevention of immune-mediated thrombotic events. For this proposal, I will aim to 1) elucidate the underlying mechanisms by which 12-LOX regulates the FcγRIIa-mediated activation in platelets. The role of 12-hydroxyeicosatetraenoic acid (12-HETE), the predominant 12-LOX oxidized lipid, and potential protein binding partners of 12-LOX will be investigated and identified in the FcγRIIa signaling pathway. These studies will provide valuable and deeper insights in the biochemical roles of 12-LOX in the FcγRIIa-mediated platelet activation pathway. Aim will 2) Characterize the role of 12-LOX in vivo by utilizing transgenic mice expressing humanized FcγRIIa and deficient in 12-LOX (hFcR/ALOX12-/-) compared to the normal 12-LOX model (hFcR/ALOX12+/+). The in vivo approaches will aid in determining whether 12-LOX proves to be an efficient target in treating and limiting immune-mediated thrombocytopenia and as well preventing thrombosis. Elucidating the underlying mechanisms by which 12- LOX and its oxylipin regulate FcγRIIa-mediated platelet function is crucial in order to accelerate the rational design of novel therapeutics for immune-mediated disorders involving incidence of thrombotic occlusion.

描述（由适用提供）：心血管疾病（CVD）是美国每年的主要死亡原因，在美国，近三分之一的死亡人数中有近1个，在美国，年度医疗保健费用超过5000亿美元。血小板介导的血栓形成是导致心血管威胁生命的临床事件的主要潜在机制，例如中风或心肌梗死一种血小板介导的血栓形式的一种形式是通过FCγRIIA的免疫复合激活（一种跨膜接收器）（一种含有大小写的ITAM）。 FCγRIIA的激活负责免疫介导的血小板减少症和血栓形成，这通常会导致接受肝素或经历败血症的患者的危及生命的心血管相关并发症。血小板12-氧化酶（12-lox）已被证明是FcγRIIA介导的血小板活化的必不可少的调节剂。但是，理解12-lox调节FcγRIIA信号传导的信号传导机制尚不清楚。理解12-lox调节该途径的信号传导机制是验证其作为预防免疫介导的血小板事件的潜在且有效的抗血域目标的关键步骤。对于此提案，我将旨在1）阐明12-lox调节FcγRIIA介导的血小板激活的基本机制。在FCγRIIIA信号通路中，将研究并鉴定12-羟基二氧化碳酸（12-HETE），主要的12-lox氧化脂质和潜在的蛋白结合伴侣的作用。这些研究将在12-lox在FcγRIIA介导的血小板激活途径中的生化作用中提供有价值，更深的见解。 AIM WILL 2）通过使用表达人源化FcγRIIA的转基因小鼠和12-LOX（HFCR/Alox12 - / - ）缺乏的转基因小鼠（与正常的12-LOX模型（HFCR/Alox12+/+）相比，还表征了12-lox在体内的作用。体内方法将有助于确定12-LOX是否证明是治疗和限制免疫介导的血小板减少症的有效目标，还可以预防血栓形成。阐明12-Lox及其Oxylipin调节FcγRIIA介导的血小板功能的潜在机制至关重要，这对于加速了涉及血栓闭塞发病率的免疫介导疾病的新型治疗方法的合理设计。