IN VIVO SIGNALING OF THE ERYTHROPOIETIN RECEPTOR

描述(申请人的描述)： 促红细胞生成素受体(EPO-R)信号对分化至关重要， 成熟红系祖细胞的增殖和存活。 EPO-R信号转导功能障碍导致恶性肿瘤和其他疾病 红系细胞，如红白血病和真性红细胞增多症。研究 在过去的几年中强调了信号通路 由生长因子受体和酪氨酸激酶受体激活 是多余的，并被许多受体共享。他们还指出， 缺乏对受体信号传导的了解 生理环境。这项提议的总体目标是 克服缺乏关于调节EPO-R的机制的信息 在正常发育过程中发出信号。 本提案中概述的研究旨在调查 MAP-K信号转导通路(ERK、JNK、p38)的参与及其作用 利用逆转录病毒基因转导胎肝细胞发育红系 来自EPO-R基因敲除小鼠。这些小鼠在胚胎中死于严重的贫血， 晚期红系祖细胞缺乏分化所致。这个 申请者将调查JNK和p38的潜在激活 (已知ERK由EPO-R参与激活)响应 EPO-R参与对细胞结果很重要，如增殖， 红系细胞的分化或存活。她也在克隆小说 细胞因子诱导的SH2-样基因可能为负性 调节EPO-R信号转导。此外，她还将调查这起事件 在红系恶性肿瘤中EPO-R信号的负调控因子 为真性红细胞增多症。在一个相关的项目中，她将研究体内的 促红细胞生成素受体酪氨酸磷酸化的作用在这个过程中，她将 利用胎肝细胞建立体内嵌合动物模型系统 从逆转录病毒转导特定EPO-R突变体的E-O-R-/-小鼠到 致死照射成年小鼠的重建红细胞生成作用。 促红细胞生成素受体信号转导及其机制的分子理解 红系血液病和恶性肿瘤的调节失调是 开发新的治疗方法，如纠正的方法 通过基因治疗的缺陷。

DESCRIPTION (Applicant's Description): Erythropoietin-Receptor (EPO-R) signaling is crucial for differentiation, proliferation and survival of mature erythroid progenitor cells. Dysfunction of EPO-R signaling results in malignancies and other disorders of erythroid cells such as erythroleukemias and polycythemia vera. Studies during the past several years have emphasized that signaling pathways activated by growth factor receptors and tyrosine kinase receptors are redundant and shared by many receptors. They have also pointed out the absence of understanding of receptor signaling in their primary physiological setting. The overall objective of this proposal is to overcome this lack of information regarding mechanisms that regulate EPO-R signaling during normal development. The studies outlined in the present proposal are aimed to investigate the involvement and the role of MAP-kinase pathways (ERK, JNK, p38) during erythroid development using retroviral gene transfer into fetal liver cells from EPO-R knock-out mice. These mice die in embryo from severe anemia, due to an absence of differentiation of late erythroid progenitor cells. The applicant will investigate whether the potential activation of JNK and p38 (ERK is known to be activated by the EPO-R engagement) in response to the EPO-R engagement is important for cellular outcomes such as proliferation, differentiation or survival of erythroid cells. She is also cloning novel Cytokine-Inducible-SH2-containing(CIS)-Like genes which may negatively regulate EPO-R signaling. In addition, she will investigate the involvement of the negative regulators of EPO-R signaling in erythroid malignancies such as polycythemia vera. In a related project she will investigate the in vivo role of tyrosine phosphorylation of the EPO-R. In this process she will establish an in vivo chimeric animal model system using fetal liver cells from E P O-R-/- mice retrovirally transduced with specific EPO-R mutants to reconstitute erythropoiesis in lethally irradiated adult mice. Molecular understanding of EPO-R signaling and its mechanisms of dysregulation in erythroid blood disorders and malignancies is essential for development of novel therapeutic approaches such as the ones that correct the defect by gene therapy.