Mouse Models of IM

IM小鼠模型

• 批准号: 7912880
• 负责人: Anna Rita Rita Migliaccio
• 金额: $ 44.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7912880
• 关键词: Abnormal Cell; Bone Marrow; Cells; Defect; Development; Disease; Disease Progression; Emperipolesis; Extramedullary; Extramedullary Hematopoiesis; Generations; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Investigation; Megakaryocytes; Membrane; Mesenchymal Stem Cells; Modeling; Mus; Myelofibrosis; Myeloproliferative disease; Osteoblasts; Patients; Peptide Hydrolases; Primary Myelofibrosis; Research; Side; Site; Staging; Stem cells; Stromal Cell-Derived Factor 1; System; Testing; cell type; drug development; human GATA1 protein; mouse model; neutrophil; peripheral blood; stem; tool; trafficking; treatment strategy

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.

我们建议使用加塔-1 low小鼠模型作为工具，以确定潜在的生物学机制， 异常造血干细胞（HSC）和祖细胞（HPC）运输和髓外 造血，特发性骨髓纤维化（IM）的特点，并确定新的目标， 治疗这种疾病的药物。在本项目中，我们将测试HSC/HPC动员发生的假设 在疾病的特定阶段，异常的细胞运输需要产生特定的 细胞类型（髓外造血起始细胞，EMH-IC）或HSC/EPC和 间充质干细胞（MSC）和/或内皮祖细胞（EPC），负责产生一种或多种细胞因子。 允许的造血微环境中的各种髓外网站。为了验证这一假设， 将： 具体目的1）为了表征HSC/HPC和MSC/EPC动员和运输的程度， 加塔-1 low小鼠骨髓纤维化的发展过程。 具体目的2）确定异常HSC/HPC运输发展的潜在机制 和加塔-1 low小鼠髓外造血。 具体目的3）确定治疗加塔-1低中疾病各阶段的治疗策略 小鼠 相关性：IM是一种与异常干细胞运输相关的血液恶性肿瘤， 髓外造血我们认为，对导致 小鼠模型中的异常HSC/HPC运输和髓外造血（项目4）和IM 患者（项目5）将代表一个强大而有效的方法，以确定最佳的治疗IM。