Role of Young Thrombocytes and Their Microparticles

描述（由申请人提供）：血小板是止血和血栓形成的重要参与者。在哺乳动物中，有两种类型的血小板，即年轻和成熟，分别携带更多和更少数量的粘附受体。血小板产生微粒，也携带这些受体。尽管在止血和血栓形成方面进行了数十年的工作，但年轻血小板及其微粒的体内功能都是未知的。斑马鱼是一个很好的模型系统来描绘年轻的血小板及其微粒的功能，因为他们拥有血小板等价物称为血小板。在我们的初步研究中，我们已经表明年轻的血小板更活跃，携带更多的受体，并在斑马鱼动脉损伤模型中首先出现在创伤部位。同样，我们已经在循环血小板微粒上鉴定出类似的受体。由于年轻的血小板更活跃，因此它们可能随后产生更活跃的微粒。这些微粒可能是第一个参与粘附反应的微粒，因为在流动的血液中在血管壁处或附近发现较小尺寸的组分的可能性更大。此外，可能的是，通过微泡脱落，年轻的血小板可能失去受体，变成活性较低的成熟血小板。因此，我们的假设是，年轻的血小板通过未知的机制产生微粒，失去它们的受体作为微泡，成为活性较低的成熟血小板，这些微粒的产生反过来可能有助于血栓沿着年轻的血小板。在这项资助申请中，我们建议建立微粒和年轻的血小板在斑马鱼的伤口部位的选择性招聘，并利用斑马鱼遗传学的力量，分离和表征斑马鱼突变体的微粒脱落缺陷。这些研究应提供深入了解血小板微粒在止血中的作用，其生产和血小板成熟的机制。

DESCRIPTION (provided by applicant): Platelets are important players in hemostasis and thrombosis. In mammals, there are two types of platelets, namely young and mature, that carry greater and less numbers of adhesive receptors respectively. Platelets produce microparticles and also carry these receptors. Despite decades of work in hemostasis and thrombosis, the in vivo function of neither young platelets nor their microparticles, is known. Zebrafish is an excellent model system to delineate functions of young platelets and their microparticles since they possess platelet equivalents called thrombocytes. In our preliminary studies, we have shown young thrombocytes are more active, carry more receptors and appear at the wounding site first in the zebrafish arterial injury model. Likewise, we have identified similar receptors on circulating thrombocyte microparticles. Since young thrombocytes are more active, it is possible that they subsequently generate more active microparticles. These microparticles may be first ones to participate in the adhesive reaction because there is a greater likelihood of finding the smaller-sized components at or near the vessel wall in flowing blood. Furthermore, it is likely that by microvesicular shedding young thrombocytes may lose the receptors and become less active mature thrombocytes. Thus, our hypothesis is that young thrombocytes generate microparticles by an unknown mechanism, lose their receptors as micro vesicles to become less active mature thrombocytes, and these microparticles generated in turn may help in the initiation of the thrombus along with young thrombocytes. In this grant application, we propose to establish the selective recruitment of microparticles and young thrombocytes to the wounding site in zebrafish and use the power of zebrafish genetics to isolate and characterize zebrafish mutants with defects in microparticle shedding. Such studies should provide insight into the role of platelet microparticles in hemostasis, mechanisms of their production and platelet maturation.