Mechanism for Thrombocytopenia in WASP and WIP Null Mice

Wiskott-Aldrich综合征是一种X连锁的血液病，其特征是 免疫缺陷、湿疹和微血小板减少症。虽然我们对WASP在 在Arp2/3复合体水平上调节肌动蛋白组装，从而增加细胞运动 戏剧性的是，在人类IS患者中观察到的微血小板减少的原因仍然是一个谜。 40年前获得的信息表明，缺乏WASP的血小板已经显著减少 与正常血小板相比，骨髓移植前循环中存活时间的比较 作为治疗血小板减少症的一种部分治疗方法，脾切除术成为治疗的首选方法。 这些病人中。最近在WASP和WIP基因敲除小鼠中的研究模拟了 人类是血小板，并揭示了它们是关键的潜在缺陷，因为WASP的功能测试为空 不同组别的血小板显示，它们的激活、分泌和扩散与正常情况一样好 血小板。我们已经制定了一种系统的方法来界定清除机制，到目前为止， 确定了两条先前未被识别的清除途径，它们检测到碳水化合物呈现在 血小板VWF受体。目标1将描述识别Wasp-/-和Wasp-/-的受体介导的途径(S) WIP-/-血小板体外和体内定量系统检测血小板去除量的研究 黄蜂-/-和WIP-/-血小板-吞噬细胞相互作用。目标2将决定如何失去 黄蜂或WIP蛋白导致血小板内肌动蛋白动力学改变。它还将确定是否 N-WASP在血小板中的累积丢失会导致细胞骨架缺陷。目标3将对这些进行补充 清除研究并调查血小板生成减少是否与WASP的疾病状态有关- /-和WIP-/-动物。因此，拟议的研究将使我们了解(S) 过早地将无效血小板从循环中移除并产生关于以下方面的基本知识 通常起作用的过程是移除衰老和受损的血小板，以及导致 将提高血小板的生物生成和存活率。

Wiskott-Aldrich Syndrome (WAS) is an X-linked hematopoietic disease that is characterized by immunodeficiency, eczema, and microthrombocytopenia. While our understanding of the role of WASP in regulating actin assembly at the level of the Arp2/3 complex and thus, cell movement has increased dramatically, the cause of the microthrombocytopenia observed in human WAS patients remains a mystery. Information derived 40 years ago established that WASP deficient platelets have markedly diminished survival times in the circulation compared to normal platelets, and before bone marrow transplantation became the therapy of choice, splenectomy was widely practiced as a partial cure for the thrombocytopenia of these patients. Recent studies in WASP and WIP knockout mice mimic the rapid clearance times of human WAS platelets and reveal them to be the key underlying defect, as functional tests of WASP null platelets by different groups have shown them to activate, secrete, and spread equally well as normal platelets. We have developed a systematic approach to define clearance mechanisms and have, thus far, identified two previously unrecognized clearance pathways that detect altered carbohydrate presentation on the platelet vWf receptor. Aim 1 will delineate the receptor-mediated pathway(s) that recognize WASP-/- and WIP-/- platelets using both quantitative in vitro and in vivo systems to measure platelet removal and to study WASP-/- and WIP-/- platelet-phagocyte interactions. Aim 2 will determine how the loss of the either the WASP or WIP protein leads to altered actin dynamics in platelets. It will also determine whether the accumulated loss of N-WASP in platelets leads to cytoskeletal defects. Aim 3 will complement these clearance studies and investigate if diminished platelet production contributes to the disease state of WASP- /- and WIP-/- animals. Therefore, the proposed studies will inform us as to the mechanism(s) that prematurely remove WAS null platelets from the circulation and generate fundamental knowledge as to processes that normally function to remove senile and damaged platelets, as well as lead to strategies that will enhance both platelet biogenesis and survival.