Mouse Models of Myelofibrosis

骨髓纤维化小鼠模型

• 批准号: 8925002
• 负责人: Anna Rita F Migliaccio
• 金额: $ 47.52万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925002
• 关键词: Animal Disease Models; Animal Model; BMP4; Biological Assay; Biology; CXCR4 gene; Cell Maturation; Cells; Cytoplasmic Granules; Defect; Development; Disease; Disease Progression; Drug Targeting; Employee Strikes; Extramedullary; Extramedullary Hematopoiesis; Failure; Funding; Gelatinase B; Gene Expression; Growth Factor; Hematopoiesis; Hematopoietic; Immunoelectron Microscopy; Inflammatory; Investigation; JAK2 gene; Lead; MMP9 gene; Marrow; Megakaryocytes; Mesenchymal Stem Cells; Mus; Myelofibrosis; Natural History; Neutrophil Activation; Osteoblasts; P-Selectin; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Primary Myelofibrosis; Proliferating; Proteins; Research; SELP gene; Signaling Molecule; Site; Sorting - Cell Movement; Stem cells; Stimulus; Testing; Thrombin; Transplantation; chemokine; design; drug development; improved; in vivo; inhibitor/antagonist; loss of function; metallothionein III; mouse model; neutrophil; prevent; receptor; research study; response; stem; trafficking; treatment strategy; von Willebrand Factor

Both hematopoietic failure and development of extramedullary hematopoiesis are associated with disease progression in patients with primary myelofibrosis (PMF). During the previous funding period, close cooperation between Project 4 and 5 led to the identification of striking similarities between stem/progenitor cell (HSC/HPC) and microenvironmental (HM) abnormalities present in PMF patients and Gatallow mice, an animal model for this disease. These abnormalities are potential targets for drug development and we have already identified plitidepsin as a drug that altered the natural history of myelofibrosis in Gatallow mice by targeting both abnormalities. This drug is presently under investigation in Project 6 for the treatment of PMF patients (MPD-RC 110). In this project, we plan to continue the fruitful interaction between Project 4 and 5 by further defining HSC/HPC and HM abnormalities associated with myelofibrosis in Gatallow mice. By transplantation assay and forced gene expression, we propose to test the hypothesis that the hematopoietic failure and development of extramedullary hematopoiesis in Gatallow mice with myelofibrosis is due to autonomous defects of HSC/HPC due to insufficient expression of CXCR4 and/or Rad (respectively the receptor and the first intracellular signaling molecule of the chemokine CXCR12 (Specific aim 1). By immuno-electron microscopy studies and loss of function experiments, we propose to test the hypothesis that, because of alterations in protein sorting into the D-granules, Gatallow MK (and possibly MK from PMF patients) stimulate mesenchymal stem cell maturation into osteoblasts impairing the ability of these cells to form a functional HM in the marrow (Specific aim 2). In addition, in vivo treatments of Gatallow mice with inhibitors of JAK2, the neutrophil protease MMP-9 and TGFD will test the hypothesis that drugs targetting abnormalities in HSC/HPC and HM of Gatal low mice will improve the natural history of myelofibrosis, alone or in combination with plitidepsin, in this animal model of the disease (Specific aim 3),

在原发性骨髓纤维化(PMF)患者中，造血衰竭和髓外造血的发展都与疾病的进展有关。在之前的资助期间，项目4和项目5之间的密切合作导致在PMF患者和这种疾病的动物模型Gatlow小鼠中发现了干细胞/祖细胞(HSC/HPC)和微环境(HM)异常之间的惊人相似之处。这些异常是药物开发的潜在靶点，我们已经确定plitidessin是一种通过针对这两种异常来改变加特罗小鼠骨髓纤维化自然历史的药物。这种药物目前正在进行项目6的研究，用于治疗PMF 患者(MPD-RC 110)。在这个项目中，我们计划继续项目4和项目5之间卓有成效的互动，通过进一步确定与加特罗小鼠骨髓纤维化相关的HSC/HPC和HM异常。通过移植试验和强制基因表达，我们建议检验这一假设，即造血 CXCR4和/或Rad(趋化因子CXCR12的受体和第一个细胞内信号分子(特异性靶点1))的表达不足导致HSC/HPC自主性缺陷，导致骨髓纤维化小鼠髓外造血功能的失败和发展。通过免疫电子显微镜研究和功能丧失实验，我们建议检验这一假设，即由于进入D颗粒的蛋白质分类的改变，Gatlow MK(可能来自PMF患者的MK)刺激间充质干细胞成熟为成骨细胞，从而削弱这些细胞在骨髓中形成功能性HM的能力(特定目标2)。此外，在体内治疗加特罗小鼠与 JAK2的抑制剂、中性粒细胞蛋白酶MMP-9和TGFD将检验这样的假设，即在这种疾病的动物模型中，针对GATAL LOW小鼠HSC/HPC和HM异常的药物单独或与plitidessin联合使用，可以改善骨髓纤维化的自然病史。