Genetic Basis of Polycythemia Vera

真性红细胞增多症的遗传基础

• 批准号: 7113537
• 负责人: JOSEF T PRCHAL
• 金额: $ 28.93万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-06 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113537
• 关键词: JAK kinase; cell line; clinical research; family genetics; gene mutation; genetic library; genotype; human subject; kinase inhibitor; loss of heterozygosity; molecular pathology; myelofibrosis; phenotype; polycythemia vera; protein protein interaction

Polycythemia vera (PV) is the most common myeloproliferative disorder. Relevance of this project to the public health is that elucidation of molecular PV defect will result in specific therapy and eventual cure of PV. Based on our previous studies, we hypothesize that PV is caused by changes in gene expression at several levels. Identification of our finding of the chromosome 9p uniparenteral disomy was reproduced and provided the basis for the recent discovery of the constitutively active mutant JAK2 V617F on chromosome 9p that is present in the majority of PV patients: JAK2 is mutated in a single allele and it is converted to homozygosity by uniparenteral disomy in approximately 30% of PV patients. However, the JAK2 V617F alteration does not fully explain the pathophysiology of PV. 1) We hypothesize that other genetic events are needed for the development of the full PV phenotype. In these studies we will pursue a) identification of positional candidates through familial co-segregation of genomic regions with the PV phenotype. b) identification of positional candidates by shared regions of genome architecture or expression changes, c) we will guide our genomic analyses by using the fund of knowledge about JAK2, its pathways and interacting proteins, and analyzing those PV patients without JAK2 V617F mutation. 2) a) We will study the cellular and biochemical effect of JAK2 V617F in cell lines and correlate these with the effect of tyrosine kinase inhibitors; similar studies will be done in polycythemic mice with JAK2 V617F in hematopoietic cells, b) We will correlate the PV clinical response (an ongoing clinical study of imatinib mesylate with Dr. Verstorvsek - see project 6) to imatinib mesylate with their JAK2 V617F genotype and expression, c) We will attempt to identify the pathophysiology of PV in those patients who respond to imatinib mesylate.

真性红细胞增多症（PV）是最常见的骨髓增生性疾病。本项目与 公共卫生的一个重要方面是，阐明PV的分子缺陷将导致特异性治疗并最终治愈PV。 基于我们以前的研究，我们假设PV是由几个基因表达的变化引起的， 程度.我们发现的染色体9 p单肠外二体性的鉴定被复制并提供 最近在染色体9 p上发现的组成型活性突变体JAK 2 V617 F的基础是， 存在于大多数PV患者中：JAK 2在单个等位基因中突变，并转化为纯合性 在约30%的PV患者中发生单肠外二体性。然而，JAK 2 V617 F的改变并不能完全解释 PV的病理生理学 1)我们推测，其他遗传事件的发展需要完整的PV表型。在 这些研究，我们将追求a）通过家庭共分离的位置候选人的识别， 具有PV表型的基因组区域。B）通过以下的共享区域识别位置候选者： 基因组结构或表达变化，c）我们将通过使用 了解JAK 2及其通路和相互作用蛋白，并分析那些没有JAK 2的PV患者 V617 F突变。 2)a）我们将研究JAK 2 V617 F在细胞系中的细胞和生物化学作用，并将这些与JAK 2 V617 F在细胞系中的作用相关联。 酪氨酸激酶抑制剂的作用;将在JAK 2 V617 F的红细胞增多症小鼠中进行类似的研究 B）我们将PV临床应答（一项正在进行的伊马替尼临床研究） 甲磺酸伊马替尼与Verstorvsek博士-见项目6）与其JAK 2 V617 F基因型甲磺酸伊马替尼， 表达，c）我们将尝试确定PV的病理生理学在那些对伊马替尼有反应的患者中 甲磺酸盐