Platelet CLEC-2 in Arterial Thrombosis

动脉血栓形成中的血小板 CLEC-2

• 批准号: 10434845
• 负责人: Lijun Xia
• 金额: $ 43.7万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434845
• 关键词: Address; Adhesions; Adverse effects; Antiplatelet Drugs; Arteries; Aspirin; Binding; Biological; Bleeding time procedure; Blood Cells; Blood Platelets; Blood Vessels; Blood flow; C-Type Lectins; Carbohydrates; Cessation of life; Chimeric Proteins; Clinical; Coagulation Process; Cytoplasmic Tail; Data; Development; Endothelium; Equilibrium; Exhibits; Extracellular Domain; FDA approved; Fc domain; Glycopeptides; Glycoproteins; Growth; Hemorrhage; Hemostatic function; Human; ITAM; Immunoglobulin G; In Vitro; Integrins; Lead; Lectin; Life; Ligands; Link; Mediating; Medicine; Modeling; Mus; Myocardial Infarction; Myocardial Ischemia; Pathogenesis; Pathologic; Pathway interactions; Patients; Platelet Activation; Platelet Glycoproteins; Platelet aggregation; Play; Polysaccharides; Proteins; Publishing; Recombinants; Risk; Role; Signal Transduction; Site; Stroke; Testing; Thrombosis; Thrombus; United States; antagonist; artery occlusion; atherosclerotic plaque rupture; base; disability; in vivo; inhibitor; injured; insight; interest; podoplanin; prevent; receptor; sialylation; side effect; targeted agent; thrombotic; von Willebrand Factor

PROJECT SUMMARY/ABSTRACT Arterial thrombotic diseases such as ischemic heart disease are the leading cause of disability and death in the United States. Platelet adhesion and formation of thrombotic platelet aggregates at the site of a ruptured atherosclerotic plaque or damaged endothelium under arterial blood flow is essential in the pathogenesis of arterial thrombosis. Under high or disturbed flow conditions, the initial interaction between platelets and the vessel wall is primarily mediated by von Willebrand factor (vWF) and platelet glycoprotein Iba (GPIba), which subsequently leads to platelet content release, aggregation, and activation of the coagulation. These mechanisms, which are critical for both hemostasis and thrombosis, are targets of current FDA-approved antiplatelet therapies. Although they are effective, all have the life-threatening side effect of causing bleeding, which significantly limits their clinical use. To address this unmet need, it is critical to further elucidate insights into mechanisms essential for thrombosis but dispensable for hemostasis. Recent published data from several independent labs show that platelet CLEC-2 (C-type lectin-like receptor 2) is important in arterial thrombosis. However, how CLEC-2 regulates arterial thrombosis is unknown. The lectin-domain of CLEC-2 is known to bind to sialylated O-glycans. Our preliminary data showed that CLEC-2 interacts with GPIba in a sialylation-dependent manner. Furthermore, our preliminary results reveal that CLEC-2 promotes GPIba- mediated activation of integrin αIIbβ3, which is critical for arterial thrombus growth and stability in vivo. Importantly, blocking CLEC-2 function does not prolong the bleeding time in vivo. Therefore, we hypothesize that CLEC-2 is critical for GPIba-mediated platelet activation that is required for arterial thrombus growth and stability. To test this, we will 1) test the hypothesis that CLEC-2 regulates GPIba-mediated platelet activation through interaction between its lectin-like domain and sialylated O-glycans of GPIba as GPIba is heavily modified by sialylated O-glycans; 2) determine if/how CLEC-2 stabilizes the arterial thrombus by facilitating GPIba-mediated integrin aIIbb3 activation using mouse and human arterial thrombosis models. CLEC-2 and GPIba are expressed at similar high levels on murine platelets, and both receptors are essential in arterial thrombosis. However, the mechanisms underlying their role in arterial thrombosis have been either elusive (GPIba) or unknown (CLEC-2). Our proposed study will provide new mechanistic insights into these outstanding questions in the field. It may lead to the development of a new effective and safe anti-thrombosis therapy.

项目总结/文摘