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.

多余细胞增多症（PV）是最常见的骨髓增生性疾病。这个项目与 公共卫生是，阐明分子PV缺陷将导致特定的治疗和最终治愈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 水平。复制并提供了我们发现9P染色体染色体染色体疾病的发现并提供的鉴定 最近发现在9p染色体上的组成型活动突变体JAK2 V617F的基础 大多数PV患者中存在：JAK2在单个等位基因中突变，并转化为纯合性 大约30％的光伏患者中的单次疾病。但是，JAK2 V617F变更并未完全解释 PV的病理生理学。 1）我们假设需要其他遗传事件来开发完整的PV表型。在 这些研究我们将通过a）通过家族共隔离来确定位置候选者 具有PV表型的基因组区域。 b）通过共享区域来识别位置候选者 基因组结构或表达变化，c）我们将使用基金来指导我们的基因组分析 有关JAK2的知识，其途径和相互作用的蛋白质，并分析没有JAK2的PV患者 V617F突变。 2）a）我们将研究JAK2 V617F在细胞系中的细胞和生化作用，并将其与 酪氨酸激酶抑制剂的作用；类似的研究将在用JAK2 V617F中的多余一只小鼠中进行 造血细胞，b）我们将关联PV临床反应（伊马替尼的临床研究 与Verstorvsek博士的梅赛酸盐 - 请参阅项目6）与其JAK2 V617F基因型和 表达，c）我们将尝试确定那些对伊马替尼反应的患者的PV的病理生理学 梅赛酸盐。