Molecular and Cellular Biology of Thrombopoietin

描述（由申请人提供）：血小板生成素（TPO）是血小板生成的主要调节剂。通过与c-Mpl受体的相互作用，TPO通过触发Jak 2的磷酸化和活化来启动信号级联。虽然这是很好地建立，它仍然不清楚TPO信号是如何调制的，这对细胞生长和分化的调节具有重要的后果。已知TPO信号传导的失调，如赋予Jak 2或c-Mpl组成型活性的突变所例示的，是先天性和获得性骨髓增生性疾病（MPD）的发展的基础，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模拟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。在这种竞争性更新中，我们建议研究TPO信号传导的调节，包括：1）c-Mpl受体响应于TPO的运输和内化，2）c-Mpl降解的调节及其对TPO信号传导的后果，以及3）TPO和促红细胞生成素（EPO）信号传导之间的功能相似性和差异。

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.