Molecular Pathogenesis of Polycythemia Vera

真性红细胞增多症的分子发病机制

• 批准号: 7023433
• 负责人: ALISON R MOLITERNO
• 金额: $ 40.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023433
• 关键词: CD34 molecule; JAK kinase; NOD mouse; SCID mouse; biological signal transduction; clinical research; gene expression; gene expression profiling; gene mutation; genetic disorder; growth factor receptors; human subject; molecular pathology; pathologic process; polycythemia vera; thrombopoietic factor

DESCRIPTION (provided by applicant): The long-term objective of this research project is to define the molecular basis of polycythemia vera (PV). We previously identified unique molecular defects in thrombopoietin (TPO) receptor (Mpl) gene expression that were associated clinically with distinct myeloproliferative phenotypes. We have now identified a JAK2 gene mutation which was also intimately associated with myeloproliferative disease clinical phenotypes in a gene dosage-dependent manner. We have also observed that gene expression profiling of PV peripheral blood (pb) CD34+ cells not only permitted the diagnosis of PV but also identified heterogeneity amongst PV patients with respect to disease behavior. Importantly, PV patients with aggressive versus indolent disease as defined by gene expression profiling exhibited different combinations of JAK2 and Mpl genetic and epigenetic defects. Thus we hypothesize that PV is a polygenic disorder and that cumulative abnormalities of the JAK2 gene and Mpl are required to generate a PV. We hypothesize that these cumulative defects are responsible for the variability of myeloproliferative disease phenotypes. We also hypothesize that mutant JAK2 gene expression and function is integrally involved on the pathogenesis of PV through aberrant signal transduction and Mpl protein processing abnormalities. To test these hypotheses, we propose to define the effect of mutated JAK2 on intracellular signal transduction and Mpl expression and function, to define the relationship between mutated JAK2 and Mpl genetic and epigenetic alterations in PV patients with respect to disease phenotype and to determine whether PV clinical phenotypes as defined by PV blood and marrow CD34+ cell gene expression profiling and JAK2/Mpl genetic defects are recapitulated by xenotransplantation of these cells in NOD/SCID mice. (End of Abstract)

描述（由申请人提供）： 该研究项目的长期目的是定义多性毛细血管Vera（PV）的分子基础。 我们先前鉴定出与临床上不同的骨髓增生性表型相关的血小板素（TPO）受体（MPL）基因表达中的独特分子缺损。现在，我们已经确定了一种JAK2基因突变，该突变也与髓增生性疾病临床表型密切相关。我们还观察到，PV外周血（PB）CD34+细胞的基因表达分析不仅允许诊断PV，而且还鉴定出PV患者在疾病行为方面的异质性。重要的是，由基因表达谱分析所定义的具有侵袭性与懒惰疾病的PV患者表现出JAK2和MPL遗传和表观遗传缺陷的不同组合。因此，我们假设PV是一种多基因疾病，并且需要JAK2基因和MPL的累积异常才能产生PV。我们假设这些累积缺陷是导致骨髓增生性疾病表型的变异性的原因。我们还假设突变的JAK2基因表达和功能与异常信号转导和MPL蛋白质加工异常积聚在PV的发病机理上。 To test these hypotheses, we propose to define the effect of mutated JAK2 on intracellular signal transduction and Mpl expression and function, to define the relationship between mutated JAK2 and Mpl genetic and epigenetic alterations in PV patients with respect to disease phenotype and to determine whether PV clinical phenotypes as defined by PV blood and marrow CD34+ cell gene expression profiling and JAK2/Mpl genetic defects are这些细胞在NOD/SCID小鼠中概括了这些细胞的异种移植。 （抽象的结尾）