Molecular Pathogenesis of Polycythemia Vera

真性红细胞增多症的分子发病机制

• 批准号: 7467901
• 负责人: ALISON R MOLITERNO
• 金额: $ 38.88万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467901
• 关键词: Behavior; Blood; CD34 gene; Cells; Defect; Diagnosis; Disease; Epigenetic Process; Exhibits; Gene Dosage; Gene Expression; Gene Expression Profiling; Gene Mutation; Genetic; Heterogeneity; Indolent; JAK2 gene; Marrow; Molecular; Mutate; Mutation; Myeloproliferative disease; Pathogenesis; Patients; Phenotype; Polycythemia Vera; Process; Proteins; Research Project Grants; SCID Mice; Signal Transduction; Testing; Thrombopoietin; Xenograft procedure; abstracting; base; clinical phenotype; disease phenotype; human MPL protein; mutant; peripheral blood

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标是确定真性红细胞增多症 (PV) 的分子基础。 我们之前发现了血小板生成素（TPO）受体（Mpl）基因表达的独特分子缺陷，这些缺陷在临床上与不同的骨髓增殖表型相关。我们现已鉴定出 JAK2 基因突变，该突变也以基因剂量依赖性方式与骨髓增殖性疾病临床表型密切相关。我们还观察到，PV 外周血 (pb) CD34+ 细胞的基因表达谱不仅可以诊断 PV，而且还可以识别 PV 患者在疾病行为方面的异质性。重要的是，根据基因表达谱定义，患有侵袭性疾病和惰性疾病的 PV 患者表现出不同的 JAK2 和 Mpl 遗传和表观遗传缺陷组合。因此，我们假设 PV 是一种多基因疾病，并且 JAK2 基因和 Mpl 的累积异常是产生 PV 所必需的。我们假设这些累积缺陷是导致骨髓增殖性疾病表型变异的原因。我们还假设突变型 JAK2 基因表达和功能通过异常信号转导和 Mpl 蛋白加工异常与 PV 的发病机制密切相关。为了检验这些假设，我们建议定义突变的 JAK2 对细胞内信号转导和 Mpl 表达和功能的影响，定义突变的 JAK2 和 Mpl 遗传和表观遗传改变在 PV 患者中与疾病表型的关系，并确定由 PV 血液和骨髓 CD34+ 细胞基因表达谱和 JAK2/Mpl 遗传缺陷定义的 PV 临床表型是否是真性红斑狼疮患者的临床表型。 通过将这些细胞异种移植到 NOD/SCID 小鼠中来概括。 （摘要完）