Mouse Models of Myelofibrosis

骨髓纤维化小鼠模型

基本信息

项目摘要

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),
原发性骨髓纤维化(PMF)患者的造血功能衰竭和髓外造血的发生与疾病进展相关。在上一个资助期间,项目4和项目5之间的密切合作导致鉴定出PMF患者和Gatallow小鼠(该疾病的动物模型)中存在的干/祖细胞(HSC/HPC)和微环境(HM)异常之间的惊人相似性。这些异常是药物开发的潜在目标,我们已经确定了plitidepsin作为一种药物,通过靶向两种异常改变了Gatallow小鼠骨髓纤维化的自然史。该药物目前正在研究项目6中用于治疗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之间富有成效的相互作用,进一步确定Gatallow小鼠中与骨髓纤维化相关的HSC/HPC和HM异常。通过移植试验和强制基因表达,我们提出了测试的假设,造血 在患有骨髓纤维化的Gatallow小鼠中,髓外造血的失败和发展是由于HSC/HPC的自主缺陷,这是由于CXCR 4和/或Rad(分别是趋化因子CXCR 12的受体和第一细胞内信号分子)表达不足引起的(具体目的1)。通过免疫电子显微镜研究和功能丧失实验,我们提出测试以下假设:由于蛋白分选到D颗粒中的改变,Gatallow MK(可能还有PMF患者的MK)刺激间充质干细胞成熟为成骨细胞,损害这些细胞在骨髓中形成功能性HM的能力(具体目的2)。此外,在Gatallow小鼠的体内治疗中, JAK 2、嗜中性粒细胞蛋白酶MMP-9和TGFD的抑制剂将检验以下假设:靶向Gatal低小鼠的HSC/HPC和HM中的异常的药物将在该疾病的动物模型中单独或与普利地辛组合改善骨髓纤维化的自然史(具体目的3),

项目成果

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Anna Rita F Migliaccio其他文献

Anna Rita F Migliaccio的其他文献

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{{ truncateString('Anna Rita F Migliaccio', 18)}}的其他基金

The human glucocorticoid receptor and normal and pathological terminal erythroid
人糖皮质激素受体与正常和病理性终末红细胞
  • 批准号:
    8550819
  • 财政年份:
    2012
  • 资助金额:
    $ 29.93万
  • 项目类别:
The human glucocorticoid receptor and normal and pathological terminal erythroid
人糖皮质激素受体与正常和病理性终末红细胞
  • 批准号:
    8416617
  • 财政年份:
    2012
  • 资助金额:
    $ 29.93万
  • 项目类别:
Mouse Models of Myelofibrosis
骨髓纤维化小鼠模型
  • 批准号:
    8064162
  • 财政年份:
    2006
  • 资助金额:
    $ 29.93万
  • 项目类别:
Mouse Models of Myelofibrosis
骨髓纤维化小鼠模型
  • 批准号:
    8533752
  • 财政年份:
    2006
  • 资助金额:
    $ 29.93万
  • 项目类别:
Mouse Models of Myelofibrosis
骨髓纤维化小鼠模型
  • 批准号:
    8925002
  • 财政年份:
    2006
  • 资助金额:
    $ 29.93万
  • 项目类别:
Project 2: Defining the role of megakaryocyte abnormalities in the progression of primary myelofibrosis
项目 2:确定巨核细胞异常在原发性骨髓纤维化进展中的作用
  • 批准号:
    10360650
  • 财政年份:
    2006
  • 资助金额:
    $ 29.93万
  • 项目类别:
Mouse Models of Myelofibrosis
骨髓纤维化小鼠模型
  • 批准号:
    8377874
  • 财政年份:
    2006
  • 资助金额:
    $ 29.93万
  • 项目类别:
CORE--TISSUE CULTURE
核心——组织培养
  • 批准号:
    6302334
  • 财政年份:
    2000
  • 资助金额:
    $ 29.93万
  • 项目类别:
CORE--TISSUE CULTURE
核心——组织培养
  • 批准号:
    6110462
  • 财政年份:
    1999
  • 资助金额:
    $ 29.93万
  • 项目类别:
CORE--TISSUE CULTURE
核心——组织培养
  • 批准号:
    6273046
  • 财政年份:
    1998
  • 资助金额:
    $ 29.93万
  • 项目类别:

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