Molecular and Cellular Biology of Thrombopoietin

血小板生成素的分子和细胞生物学

• 批准号: 7652101
• 负责人: AMY E GEDDIS
• 金额: $ 37.08万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652101
• 关键词: Accounting; Benign; Binding; Blood Platelets; Cell Line; Cell Survival; Cells; Classification; Congenital Disorders; Development; Endocytosis; Endosomes; Erythroid Cells; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Etiology; Financial compensation; Hemorrhagic Thrombocythemia; Knockout Mice; Ligands; Link; Lysosomes; MAP Kinase Gene; Measures; Megakaryocytopoieses; Modeling; Molecular and Cellular Biology; Mus; Mutate; Mutation; Myeloproliferative disease; Pathway interactions; Patients; Peptides; Phosphorylation; Phosphotyrosine; Physiology; Platelet Count measurement; Polycythemia Vera; Primary Myelofibrosis; Process; Production; Proteins; Recycling; Regulation; Residual state; Role; Signal Transduction; Surface; Thrombocytopenia; Thrombopoiesis; Thrombopoietin; Tyrosine; Ubiquitination; Work; cancer cell; cell growth regulation; cytokine; glycosylation; human MPL protein; insight; leukemia; loss of function; mimetics; multicatalytic endopeptidase complex; neoplastic; prevent; progenitor; protein protein interaction; public health relevance; receptor; receptor sensitivity; response; src Homology Region 2 Domain; tool; trafficking

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.

描述（由申请人提供）：血小板蛋白（TPO）是血小板的主要调节剂。通过与C-MPL受体的相互作用，TPO通过触发JAK2的磷酸化和激活来启动信号级联。尽管这已经建立了良好，但尚不清楚如何调节TPO信号，这对细胞生长和分化的调节产生了重要的后果。众所周知，TPO信号传导的失调，例如，突变为JAK2或C-MPL提供了组成活性，是先天性发展的基础，并获得了骨髓增生性疾病（MPDS），包括多毛细血管VERA（PV），基本的血栓性高症（ET）和IDIIPATERIBLISPIBLISPIBLISPIBLISS（ET）和IDIPATERIBLISPIBLISP（IMFIBLisis）（IMFIBLISPIBLISP）。此外，TPO-Mimetics正在成为治疗良性和肿瘤病因的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受体运输和对TPO的响应响应的内在化，2）调节C-MPL降低及其对TPO信号的后果，以及对TPO和Erythropoietin（Epo）（Epo）信号的功能相似性和差异。公共卫生相关性：在“血小板蛋白的分子和细胞生物学”的这种续签中，我们建议以我们先前关于血小板素信号传导机制的工作为基础。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蛋白和促红细胞生成素信号传导之间的功能相似性和差异。这些研究的结果将提供有关血小板素信号传导在正常和恶性细胞中的作用的新见解。