Molecular and Cellular Biology of Thrombopoietin

说明(申请人提供)：血小板生成素(TPO)是血小板生成的主要调节因子。通过与c-MPL受体的相互作用，TPO启动了JAK2的磷酸化和激活，从而启动了一系列信号级联反应。尽管这一点已经得到了很好的证实，但TPO信号是如何调节的仍然不清楚，它对细胞生长和分化的调节具有重要的后果。以JAK2或c-MPL结构活性突变为代表的TPO信号失控是先天性和获得性骨髓增生性疾病(MPD)的基础，包括真性红细胞增多症(PV)、原发性血小板增多症(ET)和特发性骨髓纤维化(IMF)。此外，TPO类似物正在成为治疗良性和肿瘤性血小板减少症患者的重要工具。在这一竞争性更新中，我们建议研究TPO信号的调节，包括：1)TPO反应中c-MPL受体的运输和内化，2)c-MPL降解的调节及其对TPO信号的影响，以及3)TPO和促红细胞生成素(EPO)信号的功能异同。公共卫生相关性：在这次更新的《血小板生成素的分子和细胞生物学》中，我们建议在我们之前关于血小板生成素信号机制的工作的基础上再接再厉。特别是，我们将研究c-MPL受体运输的生理学，调节c-MPL降解的途径，以及血小板生成素和促红细胞生成素信号之间的功能异同。这些研究的结果将为血小板生成素信号在正常和恶性细胞中的作用提供新的见解。

DESCRIPTION (provided by applicant): Thrombopoietin (TPO) is the primary regulator of thrombopoiesis. Through its interaction with the c-Mpl receptor, TPO initiates a signaling cascade by triggering the phosphorylation and activation of Jak2. Although this is well established, it remains unclear as to how TPO signaling is modulated, which has important consequences for the regulation of cell growth and differentiation. Dysregulation of TPO signaling, as exemplified by mutations conferring constitutive activity to Jak2 or c-Mpl, is known to underlie the development of congenital and acquired myeloproliferative disorders (MPDs), including polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). In addition, TPO-mimetics are emerging as important tools for the treatment of patients with thrombocytopenia of both benign and neoplastic etiologies. In this competitive renewal we propose to study the regulation of TPO signaling, including: 1) c-Mpl receptor trafficking and internalization in response to TPO, 2) regulation of c-Mpl degradation and its consequences for TPO signaling, and 3) functional similarities and differences between TPO and erythropoietin (EPO) signaling. PUBLIC HEALTH RELEVANCE: In this renewal of "The molecular and cellular biology of thrombopoeitin" we propose to build on our previous work on the mechanisms of thrombopoietin signaling. In particular we will study the physiology of c-Mpl receptor trafficking, pathways that regulate degradation of c-Mpl, and functional similarities and differences between Thrombopoietin and erythropoietin signaling. The results of these studies will provide new insights into the role of thrombopoietin signaling in normal as well as malignant cells.