Platelet Microvesicles

描述(由申请人提供)： 摘要在血小板中，磷脂酰丝氨酸(PS)仅存在于膜双层的内叶。当被某些激动剂激活时，血小板使PS外化，并提供促凝剂表面。PS的暴露伴随着富含PS的促凝血剂膜片段的释放，称为血小板源微泡。缺乏PS暴露和微泡形成会导致一种遗传性出血障碍，斯科特综合征。在与动脉或静脉血栓形成相关的情况下，已检测到微泡增加。这些关联表明，虽然它们可能是正常止血所必需的，但微泡增多容易导致血栓形成。我们已经确定乳黏附素和Del-1(发育表达基因-1)是微泡清除的介体。乳胶粘附素和Del-1存在于循环中的微泡中，并在体外以浓度依赖的方式促进巨噬细胞吞噬它们。乳胶粘附素缺乏的小鼠循环中的微泡增加，血浆中凝血酶的生成增加。此外，在光染料诱导的内皮细胞损伤/血栓形成模型中，乳胶粘附素缺陷小鼠与野生型斜发对照组相比，血栓形成倾向增加。本研究的目标是明确微泡清除的机制(S)及其与血栓形成的关系。在抗磷脂抗体综合征中，我们还将检验这样一种假设，即每个SH的微泡清除障碍会导致高凝状态。这项建议的具体目的是进一步表征乳胶粘附素和Del-1在体内清除微泡中的作用，并验证微泡导致抗磷脂综合征血栓形成的假说。

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.