Erythropoietin receptor signaling in stress erythropoiesis and erythrocytosis

应激性红细胞生成和红细胞增多中的促红细胞生成素受体信号传导

• 批准号: 10311980
• 负责人: LILY JUNSHEN HUANG
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2023-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311980
• 关键词: Affect; Anemia; Blood Substitutes; CFU-E; Cell Death; Cell Proliferation; Cell surface; Complex; Critical Pathways; Cytoplasmic Tail; Data; Development; Dinoprostone; Distal; EPOR gene; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Etiology; Flow Cytometry; Funding; Goals; Hematologic Neoplasms; Hematopoietic; Hemorrhage; Human; Hypersensitivity; Hypoxia; IGF1 gene; IGF1R gene; IRS2 gene; In Vitro; JAK2 gene; Lead; Light; Molecular; Mus; Myeloproliferative disease; Names; Natural regeneration; Oncogenic; Pathologic; Pathway interactions; Persons; Polycythemia; Polycythemia Vera; Population; Production; Proteins; Proto-Oncogene Protein c-kit; Publishing; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stress; System; Testing; Therapeutic Agents; Tyrosine; Wild Type Mouse; Work; beta catenin; biological adaptation to stress; design; effective therapy; erythroid differentiation; experimental study; improved; in vivo; knowledge base; mouse model; mutant; novel; novel therapeutic intervention; novel therapeutics; preservation; progenitor; receptor; recruit; response; transcriptome sequencing

PROJECT SUMMARY Erythropoietin (Epo) and its receptor EpoR are primary regulators of erythropoiesis. Normal Epo levels support basal erythropoiesis. In anemia, blood loss, or hypoxia, Epo levels rise, initiating signaling pathways to expand erythroid progenitors, increasing red cell production during the erythropoietic stress response. In published work, we showed that the constitutively active JAK2 mutant JAK2(V617F), found in myeloproliferative neoplasms, needs to associate with the EpoR to transmit oncogenic signaling in erythroid progenitors to drive erythrocytosis. While EpoR signaling in more differentiated erythroid precursors has been extensively studied, EpoR signaling in early progenitors, which controls stress erythropoiesis and erythrocytosis, has not been elucidated. In preliminary studies, we show that JAK2(V617F) oncogenic signaling requires the distal EpoR cytoplasmic domain. Because this distal EpoR domain is essential for stress erythropoiesis but dispensable for basal erythropoiesis, JAK2(V617F) may hijack EpoR- dependent stress erythropoiesis pathways to drive erythrocytosis. Using a new flow cytometry strategy, we identified a previously unrecognized population of early colony- forming erythroid progenitors (CFU-E), which we named stress CFU-E or sCFU-E, as a specific target of both the JAK2(V617F)-driven signals and the stress erythropoietic response. Elucidating EpoR signaling that supports sCFU-E expansion may reveal new therapeutic avenues that can target erythrocytosis while sparing normal erythropoiesis. The central goal of this proposal is to characterize the EpoR-dependent mechanisms that drive sCFU-E expansion in stress erythropoiesis and in JAK2(V617F)-driven erythrocytosis. Aim 1 determines mechanisms and EpoR signaling in sCFU-E expansion. Aim 2 leverages our new RNA-seq data to examine novel regulators downstream of EpoR in stress erythropoiesis, murine erythrocytosis and human polycythemia vera. Together, these results will elucidate mechanisms controlling stress erythropoiesis and pathological erythrocytosis, and may lead to novel therapeutic interventions.

项目摘要 促红细胞生成素（EPO）及其受体EPOR是促红细胞生成的主要调节剂。 正常的EPO水平支持基础红细胞生成。在贫血，失血或缺氧中，EPO 水平上升，启动信号通路以扩大红斑祖细胞，增加红色 细胞产生促红细胞胁迫应力反应。在已发表的工作中，我们展示了 在骨髓增生性中发现的组成型活性JAK2突变体JAK2（V617F） 肿瘤需要与EPOR相关联，以在 促进红细胞增多的红细胞祖细胞。而Epor信号在更分化的 红细胞前体已被广泛研究，早期祖细胞中的Epor传导， 控制压力红细胞生成和红细胞增多症，尚未阐明。 在初步研究中，我们表明JAK2（V617F）致癌信号需要 远端Epor细胞质结构域。因为这个远端的Epor结构域对于压力至关重要 促红细胞生成，但对于基础红细胞生成，JAK2（v617f）可能会劫持 - 可能会劫持epor- 依赖性压力红细胞生成途径以驱动红细胞增多症。使用新流程 细胞仪策略，我们确定了先前未识别的早期菌落的人群 形成红细胞祖细胞（CFU-E），我们将其命名为应力CFU-E或SCFU-E， JAK2（V617F）驱动信号和压力红细胞生成的特定目标 回复。 阐明支持SCFU-E扩展的Epor信号传导可能会揭示新的治疗性 可以靶向红细胞增多症的途径，同时保留正常的红细胞生成。中央 该建议的目标是表征驱动EPOR的机制 压力红细胞生成和JAK2（V617F）驱动的红细胞增多症中的SCFU-E扩展。 AIM 1确定SCFU-E扩展中的机制和EPOR信号传导。目标2 利用我们的新RNA-seq数据检查EPOR下游的新型调节剂 压力性红细胞生成，鼠红细胞增多和人类多余细胞增多症。一起， 这些结果将阐明控制压力红细胞生成的机制和 病理红细胞增多症，可能导致新的治疗干预措施。