Molecular and Cellular Biology of Thrombopoietin

血小板生成素的分子和细胞生物学

• 批准号: 7624000
• 负责人: AMY E GEDDIS
• 金额: $ 23.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624000
• 关键词: Accounting; Benign; Binding; Blood Platelet Disorders; Blood Platelets; Cell Line; Cell Survival; Cells; Classification; Condition; Congenital Disorders; Cytokine Signaling; Development; Down-Regulation; Endocytosis; Endosomes; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Etiology; Event; Financial compensation; Focal Adhesion Kinase 1; Hematologic Neoplasms; Hemorrhagic Thrombocythemia; Homologous Gene; Link; Lysosomes; Measures; Megakaryocytes; Megakaryocytopoieses; Modeling; Molecular and Cellular Biology; Mus; Mutate; Mutation; Myeloproliferative disease; Pathway interactions; Patients; Peptides; Personal Satisfaction; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Phosphotyrosine; Physiology; Platelet Count measurement; Polycythemia Vera; Primary Myelofibrosis; Process; Production; Proteins; Recycling; Regulation; Residual state; Role; Signal Pathway; Signal Transduction; Surface; Thrombocytopenia; Thrombopoiesis; Thrombopoietin; Tyrosine; Ubiquitination; cell growth regulation; cytokine; glycosylation; human MPL protein; loss of function; mimetics; neoplastic; prevent; protein protein interaction; receptor; receptor sensitivity; response; src Homology Region 2 Domain; src-Family Kinases; tensin; thrombocytosis; tool; trafficking; ubiquitin ligase

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) negative regulation of TPO signaling, including the potential effects of receptor ubiquitination, Src family kinases and phosphatase and tensin homologue (PTEN) for megakaryopoiesis, and 3) functional similarities and differences between TPO and erythropoietin (EPO) signaling.

血小板生成素（TPO）是血小板生成的主要调节因子。通过其 TPO与c-Mpl受体相互作用，通过触发细胞内的信号传导， 磷酸化和激活Jak 2。虽然这是既定的，但它仍然是 不清楚TPO信号是如何调节的，这对 细胞生长和分化的调节。TPO信号转导失调，如 例如赋予Jak 2或c-Mpl组成型活性的突变，已知 先天性和后天性骨髓增生性疾病的基础 （MPD），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模拟物正在成为重要的 用于治疗良性和肿瘤性血小板减少症患者的工具 病因学在这次竞争性续约中，我们建议研究TPO的监管 信号传导，包括：1）响应TPO的c-Mpl受体运输和内化， 2)TPO信号的负调节，包括受体的潜在作用 泛素化，Src家族激酶和磷酸酶和张力蛋白同源物（PTEN）， 巨核细胞生成，以及3）TPO和 促红细胞生成素（EPO）信号传导。