SIGNAL TRANDUCTION IN POLYCYTHEMIA VERA

描述：我们研究的长期目标是确定 机制负责真性红细胞增多症（PV），一种克隆性疾病， 病因不明，涉及红细胞、髓细胞和巨核细胞 祖细胞 我们实验室最近的研究表明，PV 红系祖细胞，与正常红系祖细胞相反 细胞，对与促红细胞生成素（EPO）相关的细胞凋亡具有抗性， 剥夺 我们还发现了一种新的信号转导缺陷， 涉及血小板生成素（TPO）介导的蛋白酪氨酸的PV血小板 磷酸化 这些观察结果具有重要意义， 关于PV的发病机制及其临床表现。 根据我们迄今为止的观察，我们现在计划研究TPO介导的PV 血小板c-Mpl表达方面的血小板信号转导， 与PV血小板相比，PV巨核细胞中c-Mpl的相互作用。 到 使用液体，确定PV中的抗凋亡机制 悬浮培养系统能够扩大正常细胞的数量 和PV外周血红系祖细胞，我们计划检查 Bcl-2家族基因的表达和调控机制 和p53在EPO的存在和不存在下，并使用中性粒细胞作为 骨髓细胞的替代模型，以确定是否 生长因子剥夺相关的抗肿瘤作用及其机制 机制是PV造血的整体特征。

DESCRIPTION: The long term objective of our research is to define the mechanisms responsible for polycythemia vera (PV), a clonal disorder of unknown etiology which involves erythroid, myeloid and megakaryocytic progenitor cells. Recent studies in our laboratory have indicated that PV erythroid progenitor cells, in contrast to normal erythroid progenitor cells, are resistant to the apoptosis associated with erythropoietin (EPO) deprivation. We have also identified a novel signal transduction defect in PV platelets involving thrombopoietin (TPO)-mediated protein tyrosine phosphorylation. These observations have important implications with respect to both the pathogenesis of PV and its clinical manifestations. Based on our observations to date, we now plan to examine TPO-mediated PV platelet signal transduction with respect to platelet c-Mpl expression, the interaction of c-Mpl in PV megakaryocytes as compared to PV platelets. To identify the mechanisms for apoptosis-resistance in PV, using a liquid suspension culture system capable of expanding the population of both normal and PV peripheral blood erythroid progenitor cells, we plan to examine the mechanisms involved in the expression and regulation of Bcl-2 family genes and p53 in the presence and absence of EPO, and using neutrophils as a surrogate model for myeloid cells, to determine whether the apoptosis-resistance associated with growth factor deprivation and its mechanism are global characteristics of PV hematopoiesis.