Mechanism for Thrombocytopenia in WASP and WIP Null Mice

Wiskott-Aldrich综合征（WAS）是一种X连锁造血系统疾病，其特征在于： 免疫缺陷、湿疹和微血小板减少症。虽然我们对WASP在 在Arp 2/3复合物水平调节肌动蛋白组装，因此，细胞运动增加 引人注目的是，在人WAS患者中观察到的微小血小板减少症的原因仍然是个谜。 40年前的信息表明，WASP缺乏的血小板显著减少， 与正常血小板相比，以及在骨髓移植前， 作为首选的治疗方法，脾切除术被广泛用作血小板减少症的部分治愈方法。 这些病人。最近在WASP和WASP基因敲除小鼠中的研究模拟了 人WASP血小板，并揭示他们是关键的潜在缺陷，作为WASP无效的功能测试 不同人群的血小板显示它们的活化、分泌和扩散与正常人一样好 血小板我们制定了一个系统的办法来界定清除机制，迄今为止， 确定了两种以前未被认识的清除途径， 血小板vWf受体。目的1将描述识别WASP-/-和 使用定量体外和体内系统测量血小板清除并研究血小板清除率， WASP-/-和β-/-血小板-吞噬细胞相互作用。目标2将决定如何损失或 WASP或WASP蛋白导致血小板中肌动蛋白动力学改变。它还将决定 血小板中N-WASP的累积损失导致细胞骨架缺陷。目标3将补充这些内容 清除研究，并调查血小板生成减少是否有助于WASP的疾病状态， /-和/-动物。因此，拟议的研究将告知我们， 过早地从循环中清除WAS无效血小板，并获得关于以下方面的基本知识： 这些过程通常用于清除衰老和受损的血小板，并导致 将增强血小板的生物生成和存活。

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.