Mechanism for Thrombocytopenia in WASP and WIP Null Mice

WASP 和 WIP 无效小鼠血小板减少的机制

• 批准号: 8148004
• 负责人: John H Hartwig
• 金额: $ 37.67万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8148004
• 关键词: Actins; Animals; Biogenesis; Biological Assay; Blood Circulation; Blood Platelets; Bone Marrow Transplantation; Carbohydrates; Complement; Complex; Cytoskeletal Modeling; Defect; Discontinuous Capillary; Disease; Eczema; Excision; Family; Family member; Hematopoietic; Human; Immunologic Deficiency Syndromes; In Vitro; Ingestion; Knockout Mice; Knowledge; Lead; Life; Link; Measures; Mediating; Megakaryocytes; Metabolic Clearance Rate; Mus; Pathway interactions; Patients; Phagocytes; Process; Production; Proteins; Publishing; Role; Site-Directed Mutagenesis; Splenectomy; Surface; System; Testing; Thrombocytopenia; Time; Transgenic Mice; Wiskott-Aldrich Syndrome; Work; base; cell motility; glycosylation; in vivo; macrophage; protein function; receptor; time use

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.

Wiskott-Aldrich综合征（WAS）是一种X连锁的造血疾病，其特征是 免疫缺陷，湿疹和微骨细胞减少症。虽然我们对黄蜂的作用的理解 调节肌动蛋白在ARP2/3复合物的水平上，因此细胞运动增加了 在人类中观察到的小骨细胞减少症的原因是患者仍然是个谜。 40年前得出的信息确定，黄蜂缺乏血小板明显减少 与正常血小板相比，循环中的生存时间和骨髓移植之前 成为选择的疗法，脾切除术被广泛实施，以治愈血小板减少症 这些患者。 WASP和WIP敲除小鼠的最新研究模仿了快速清除时间 人类是血小板，并揭示它们是WASP NULL的功能测试的关键基础缺陷 不同群体的血小板表明它们激活，分泌和传播与正常相同 血小板。我们已经开发了一种系统的方法来定义清除机制，到目前为止 确定了两种先前未认可的清除途径，这些通路检测到碳水化合物的发生变化 血小板VWF受体。 AIM 1将描绘识别WASP - / - 和的受体介导的途径 WIP - / - 使用定量体外和体内系统的血小板来测量血小板去除并研究 黄蜂 - / - 和WIP - / - 血小板 - 斑点相互作用。 AIM 2将决定如何损失 黄蜂或WIP蛋白会导致血小板中的肌动蛋白动力学改变。它还将确定是否 血小板中N-WASP的积累损失导致细胞骨架缺陷。 AIM 3将补充这些 清除研究并研究血小板产生是否有助于黄蜂的疾病状态 / - 和WIP - / - 动物。因此，拟议的研究将告知我们有关的机制 过早去除的是流通中的无效血小板，并产生有关的基本知识 通常起作用的过程可以消除老年和损坏的血小板，并导致策略 将增强血小板生物发生和生存。