Mouse Models of IM

IM小鼠模型

• 批准号: 7113544
• 负责人: Anna Rita Rita Migliaccio
• 金额: $ 19.35万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-06 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113544
• 关键词: bone marrow; cell migration; cellular pathology; genetic models; genetically modified animals; hematopoiesis; hematopoietic stem cells; laboratory mouse; myelofibrosis; polycythemia vera; transcription factor

We propose to use the GATA-1low murine model as a tool to define the biologic mechanisms underlying the abnormal hematopoietic stem cell (HSC) and progenitor cell (HPC) trafficking and extramedullary hemopoiesis that characterizes idiopathic myelofibrosis (IM) and identify new targets for the development of drugs to treat this disorder. During this project we will test the hypothesis that HSC/HPC mobilization occurs at specific stages of the disease and that abnormal cell trafficking requires either the generation of a specific cell type (the extramedullary hematopoietic initiating cell, EMH-IC) or mobilization of both HSC/EPC and mesenchymal stem cells (MSC) and/or endothelial progenitor cells (EPC), responsible for generating a permissive hematopoietic microenvironment in a variety of extramedullary sites. To test this hypothesis we will: Specific Aim 1) To characterize the degree of HSC/HPC and MSC/EPC mobilization and trafficking during the course of the development of myelofibrosis in GATA-1low mice. Specific Aim 2) To identify the mechanisms underlying the development of abnormal HSC/HPC trafficking and extramedullary hemopoiesis in GATA-1low mice. Specific Aim 3) To identify treatment strategies for the treatment of each stage of the disease in GATA-1low mice. Relevance: IM is a hematological malignancy associated with abnormal stem cell trafficking and increased extramedullary hematopoiesis. We believe that a side-by-side investigation of the mechanisms leading to abnormal HSC/HPC trafficking and extramedullary hematopoiesis in the mouse model (Project 4) and IM patients (Project 5) will represent a powerful and effective approach to identify the optimal treatment for IM.

我们建议使用GATA-1low小鼠模型作为一种工具来定义 造血干细胞(HSC)和造血祖细胞(HPC)运输异常与髓外 以特发性骨髓纤维化(IM)为特征的造血功能及其发展的新靶点 治疗这种疾病的药物。在这个项目中，我们将检验HSC/HPC动员发生的假设 在疾病的特定阶段，异常的细胞贩运需要产生特定的 细胞类型(髓外造血启动细胞，EMH-IC)或动员HSC/EPC和 间充质干细胞(MSC)和/或内皮祖细胞(EPC)负责产生 各种髓外部位可容许的造血微环境。为了检验这一假设，我们 将： 具体目标1)确定HSC/HPC和MSC/EPC动员和贩运的程度 GATA-1low小鼠骨髓纤维化的发生发展过程。 具体目标2)查明导致不正常的高碳钢/高碳钢贩运的机制 GATA-1低鼠骨髓外造血功能。 具体目标3)确定GATA-1 Low中疾病每个阶段的治疗策略 老鼠。 相关性：IM是一种血液系统恶性肿瘤，与干细胞的异常转运和增加有关 髓外造血。我们认为，对导致 小鼠模型(方案4)和IM中HSC/HPC的异常转运和髓外造血 患者(项目5)将代表一个强大而有效的方法来确定IM的最佳治疗方法。