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连锁造血疾病，其特征为