ROLE OF THE PNH PHENOTYPE IN LEUKEMIC TRANSFORMATION

PNH 表型在白血病转化中的作用

基本信息

  • 批准号:
    6686380
  • 负责人:
  • 金额:
    $ 30.59万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2001
  • 资助国家:
    美国
  • 起止时间:
    2001-01-20 至 2005-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (adapted from the applicant's abstract): Paroxysmal nocturnal hemoglobinuria (PNH) is a blood disorder, which is caused by the clonal expansion of a hematopoietic progenitor cell that carries a somatic mutation in the X-linked PIGA gene. It presented classically with hemoglobinuria due to intravascular hemolysis, thrombotic complications, and pancytopenia. The PIGA gene encodes a protein subunit of a glycosyltransferase essential in the synthesis of glycosyl phosphatidylinositol (GPI) anchor molecules. Patients with PNH therefore have a proportion of blood cells deficient in all GPI-linked surface molecules. PNH is frequently found in patients with aplastic anemia (AA) and in patients with myelodysplasia (MDS). Although not a neoplastic disease on its own, patients with PNH have an increased risk of developing acute myeloid leukemia (AML). Promoted by the clinical association of PNH with AA, MDS, and AML, we raised the hypothesis that a PIGA gene mutation alone does not cause clonal expansion or leukemic transformation. But due to their inability to like certain proteins to the cell surface through a GPI-anchor PNH cells escape immuno surveillance and cell death that causes bone marrow aplasia in AA and controls neoplastic cell growth in early leukemogenesis. In the proposed research we will use a mouse model that closely mimics the human disease and investigate the association of PNH with MDS and AML. We will obtain mice with blood cells lacking GPI-linked proteins by disrupting the murine Piga gene in early hematopoietic progenitor cells in the bone marrow using the Cre-loxP system. By this approach we will generate two types of mice, one with all blood cells deficient in GPI-linked proteins whereas the other will have both PIGA (+) and PIGA(-) circulating blood cells. We will then compare PIGA(+) and PIGA(-) hematopoiesis in these mice in vitro and in vivo under a variety of circumstances, including the administration of stimuli that trigger cell death along with agents known to cause leukemia transformation. Competition between cells expressing wild type Piga and those expressing the recombined Piga allele will enable us to uncover even subtle differences in cell death and proliferation in any stages of hematopoietic differentiation. These experiments will demonstrate whether PIGA(-) blood cells are more resistant to specific stimuli that activate apoptotic cell death and whether mice with PIGA(-) blood cells develop leukemia earlier and more frequent compared to mice with phenotypically normal blood cells. In this way we hope to identify the factors that differentially influence growth and death of PNH and normal hematopoietic progenitor cells and to elucidate mechanisms that may lead to leukemia transformation in patients with PNH. The availability of a mouse model for PNH will provide us with a powerful tool to test new therapeutic agents for the treatment of PNH, PNH/MDS, PNH,AML and possibly other clonal blood disorders.
描述(改编自申请人摘要):阵发性夜间发作 血红蛋白尿症(PNH)是一种血液疾病,它是由克隆性 扩增携带体细胞突变的造血祖细胞, X连锁的PIGA基因它表现为典型的血红蛋白尿, 血管内溶血、血栓形成并发症和全血细胞减少。PIGA 该基因编码一种糖基转移酶的蛋白质亚基,该糖基转移酶在该细胞中是必需的。 糖基磷脂酰肌醇(GPI)锚分子合成。患者 因此,PNH患者的血细胞比例在所有GPI相关的 表面分子PNH常见于再生障碍性贫血患者 (AA)和骨髓增生异常(MDS)患者。虽然不是肿瘤 PNH患者患PNH的风险增加, 急性髓性白血病(AML)。 由于PNH与AA、MDS和AML的临床相关性,我们提出了 PIGA基因突变本身不会引起克隆扩增的假设 或白血病转化。但由于它们无法喜欢某些蛋白质 通过GPI锚定到细胞表面的PNH细胞逃避免疫监视 和细胞死亡,导致AA骨髓再生障碍性贫血, 白血病早期的细胞生长 在拟议的研究中,我们将使用一种小鼠模型, 研究PNH与MDS和AML的关系。我们将 获得缺乏GPI连接蛋白的血细胞的小鼠, 小鼠骨髓中早期造血祖细胞中的Piga基因 使用Cre-loxP系统。通过这种方法,我们将产生两种类型的小鼠, 一种是所有的血细胞都缺乏GPI连接蛋白,而另一种是 将同时具有PIGA(+)和PIGA(-)循环血细胞。然后我们将 比较PIGA(+)和PIGA(-)小鼠体内、体外造血情况 在各种情况下,包括给予刺激, 引发细胞死亡沿着已知导致白血病转化的试剂。 表达野生型Piga的细胞与表达 重组的Piga等位基因将使我们能够发现即使是细微的差异, 在造血分化的任何阶段的细胞死亡和增殖。 这些实验将证明PIGA(-)血细胞是否比正常人更多。 对激活凋亡细胞死亡的特定刺激具有抗性, 具有PIGA(-)血细胞的小鼠更早和更频繁地患白血病 与正常血细胞的小鼠相比。我们希望通过这种方式 确定不同影响PNH生长和死亡的因素, 正常造血祖细胞,并阐明可能导致 PNH患者的白血病转化。提供鼠标 PNH的模型将为我们提供一个强有力的工具,以测试新的治疗方法, 用于治疗PNH、PNH/MDS、PNH、AML和可能的其它克隆性白血病的药剂 血液疾病

项目成果

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Monica Bessler其他文献

Monica Bessler的其他文献

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{{ truncateString('Monica Bessler', 18)}}的其他基金

DIFFERENCES IN THE PROTEIN SIGNATURES/PNH PLATELETS
蛋白质特征/PNH 血小板的差异
  • 批准号:
    8361364
  • 财政年份:
    2011
  • 资助金额:
    $ 30.59万
  • 项目类别:
CHANGES IN THE RBC PROTEOME DURING HEALTH AND DISEASE
健康和疾病期间红细胞蛋白质组的变化
  • 批准号:
    8537911
  • 财政年份:
    2010
  • 资助金额:
    $ 30.59万
  • 项目类别:
CHANGES IN THE RBC PROTEOME DURING HEALTH AND DISEASE
健康和疾病期间红细胞蛋白质组的变化
  • 批准号:
    7887839
  • 财政年份:
    2010
  • 资助金额:
    $ 30.59万
  • 项目类别:
CHANGES IN THE RBC PROTEOME DURING HEALTH AND DISEASE
健康和疾病期间红细胞蛋白质组的变化
  • 批准号:
    8723376
  • 财政年份:
    2010
  • 资助金额:
    $ 30.59万
  • 项目类别:
CHANGES IN THE RBC PROTEOME DURING HEALTH AND DISEASE
健康和疾病期间红细胞蛋白质组的变化
  • 批准号:
    8143519
  • 财政年份:
    2010
  • 资助金额:
    $ 30.59万
  • 项目类别:
DIFFERENCES IN THE PROTEIN SIGNATURES/PNH PLATELETS
蛋白质特征/PNH 血小板的差异
  • 批准号:
    8168717
  • 财政年份:
    2010
  • 资助金额:
    $ 30.59万
  • 项目类别:
CHANGES IN THE RBC PROTEOME DURING HEALTH AND DISEASE
健康和疾病期间红细胞蛋白质组的变化
  • 批准号:
    8326555
  • 财政年份:
    2010
  • 资助金额:
    $ 30.59万
  • 项目类别:
DIFFERENCES IN THE PROTEIN SIGNATURES/PNH PLATELETS
蛋白质特征/PNH 血小板的差异
  • 批准号:
    7953944
  • 财政年份:
    2009
  • 资助金额:
    $ 30.59万
  • 项目类别:
DIFFERENCES IN THE PROTEIN SIGNATURES/PNH PLATELETS
蛋白质特征/PNH 血小板的差异
  • 批准号:
    7721527
  • 财政年份:
    2008
  • 资助金额:
    $ 30.59万
  • 项目类别:
Ribosome Biogenesis in Diamond Blackfan Anemia
钻石黑扇贫血症中的核糖体生物发生
  • 批准号:
    7129299
  • 财政年份:
    2006
  • 资助金额:
    $ 30.59万
  • 项目类别:

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