Platelet Microvesicles

描述（由申请人提供）： 摘要磷脂酰丝氨酸（PS）在血小板膜双分子层的内叶中是唯一存在的。在用一些激动剂活化后，血小板使PS外化并提供促凝血剂表面。PS的暴露伴随着富含PS的促凝血膜片段的释放，称为血小板衍生的微泡。PS暴露和微泡形成的缺乏导致遗传性出血性疾病，斯科特综合征。在与动脉或静脉血栓形成相关的条件下已经检测到微泡增加。这些相关性表明，虽然它们可能是正常止血所必需的，但升高的微泡易于血栓形成。我们已经确定了lactadherin和Del-1（发育表达位点-1）作为微泡清除的介质。Lactadherin和Del-1存在于循环微泡中，并在体外以浓度依赖性方式促进巨噬细胞对其的吞噬作用。Lactadherin缺陷小鼠循环中的微泡增加，血浆中凝血酶生成增加。此外，在光染料诱导的内皮细胞损伤/血栓形成模型中，与野生型同窝对照相比，乳凝集素缺陷小鼠具有增加的血栓形成倾向。我们在当前提案中的目标是定义微泡清除的机制及其与血栓形成的关系。我们还将检验抗磷脂抗体综合征中微泡清除障碍导致高凝状态的假设。该提案的具体目的是进一步表征乳凝集素和Del-1在体内清除微泡中的作用，并检验微泡导致抗磷脂综合征血栓形成的假设。 公共卫生相关性： 当血小板被激活时，它们会释放称为微泡的小膜碎片。这些囊泡促进血液凝固，一些患有血栓形成的个体血液中的微囊泡增加。我们将测试这些微泡是否会因为清除缺陷而导致血液凝固。血栓形成的后果，如心肌梗死，中风和外周动脉闭塞是退伍军人发病率和死亡率的主要原因。我们的研究对了解血小板衍生微泡在动脉粥样硬化血栓形成中的作用有重要意义。

DESCRIPTION (provided by applicant): Abstract In platelets, phosphatidylserine (PS) is present exclusively in the inner leaflet of the membrane bilayer. Upon activation with some agonists, platelets externalize PS and provide a procoagulant surface. Exposure of PS is accompanied by the release of PS-rich procoagulant membrane fragments called platelet-derived microvesicles. Deficiency of PS exposure and microvesiculation leads to an inherited bleeding disorder, Scott syndrome. Increased microvesicles have been detected in conditions associated with either arterial or venous thrombosis. These associations suggest that, while they may be necessary for normal hemostasis, elevated microvesicles predispose to thrombosis. We have identified lactadherin and Del-1 (developmentally expressed locus-1) as mediators of microvesicles clearance. Lactadherin and Del-1 are present in circulating microvesicles and promotes their phagocytosis by macrophages in a concentration-dependent manner in vitro. Lactadherin-deficient mice have increased microvesicles in the circulation and an enhanced thrombin generation in their plasma. Furthermore, in a light-dye-induced endothelial cell injury/thrombosis model, lactadherin-deficient mice have increased thrombotic tendency compared to wild type littermate controls. Our goals in the current proposal are to define the mechanism(s) of microvesicles clearance and its relation to thrombosis. We will also test the hypothesis that impaired clearance of the microvesicles per sh leads to a hypercoagulable state in antiphospholipid antibody syndrome. The specific aims of this proposal are to further characterize the role of lactadherin and Del-1 in the clearance of microvesicles in vivo and to test the hypothesis that microvesicles causes thrombosis in antiphospholipid syndrome. PUBLIC HEALTH RELEVANCE: Narrative When platelets are activated, they release small membrane fragments called microvesicles. These vesicles promote blood clotting and some individuals with thrombosis have increased microvesicles in their blood. We will test whether these microvesicles causes blood clotting because of defective clearance. Consequences of thrombosis such as myocardial infarction, stroke and peripheral arterial occlusion are the leading causes of morbidity and mortality among veterans. Our research has a major bearing on the understanding of the role of platelet-derived microvesicles in atherothrombosis.