SIGNAL TRANDUCTION IN POLYCYTHEMIA VERA

描述：我们研究的长期目标是定义 真性红细胞增多症(PV)的发病机制 病因不明，涉及红系、髓系和巨核细胞 祖细胞。我们实验室最近的研究表明，光伏 红系祖细胞与正常红系祖细胞的对比 细胞，抵抗与促红细胞生成素(EPO)相关的凋亡 剥夺。我们还发现了一种新的信号转导缺陷 血小板生成素(TPO)介导的蛋白酪氨酸参与的PV血小板 磷酸化。这些观察结果具有重要的意义 对PV的发病机制及其临床表现进行了探讨。 根据我们到目前为止的观察，我们现在计划检查TPO介导的光伏 与血小板c-MPL表达有关的血小板信号转导 C-mpl在PV巨核细胞和PV血小板中的相互作用。至 使用一种液体，确定PV中抗细胞凋亡的机制 悬浮培养系统能够扩大两者的正常种群 和PV外周血中的红系祖细胞，我们计划检测 Bcl-2家族基因表达调控机制的研究进展 和P53在EPO存在和不存在的情况下，并使用中性粒细胞作为 髓系细胞的替代模型，以确定是否 与生长因子剥夺相关的细胞凋亡抵抗及其机制 机制是PV造血的全局性特征。

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.