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

基本信息

批准号：
10091502
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
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091502
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 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

项目摘要

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.

项目概要促红细胞生成素 (Epo) 及其受体 EpoR 是红细胞生成的主要调节因子。正常的 EPO 水平支持基础红细胞生成。在贫血、失血或缺氧时，Epo 水平上升，启动信号通路以扩大红系祖细胞，增加红色红细胞生成应激反应期间的细胞生成。在已发表的作品中，我们展示了在骨髓增殖性细胞中发现了组成型活性 JAK2 突变体 JAK2(V617F) 肿瘤，需要与 EpoR 结合来传递致癌信号红细胞祖细胞驱动红细胞增多。而 EpoR 信号传导更加分化红系前体细胞已被广泛研究，早期祖细胞中的 EpoR 信号传导，控制应激性红细胞生成和红细胞增多的机制尚未阐明。在初步研究中，我们表明 JAK2(V617F) 致癌信号传导需要远端 EpoR 胞质结构域。因为这个远端 EpoR 结构域对于压力至关重要红细胞生成但对于基础红细胞生成是可有可无的，JAK2（V617F）可能会劫持 EpoR- 依赖应激红细胞生成途径来驱动红细胞增多。使用新流程细胞计数策略，我们鉴定了一个以前未被识别的早期菌落群体形成红细胞祖细胞 (CFU-E)，我们将其命名为应激 CFU-E 或 sCFU-E，作为 JAK2(V617F) 驱动信号和应激红细胞生成的特定目标回复。阐明支持 scFU-E 扩增的 EpoR 信号传导可能会揭示新的治疗方法可以靶向红细胞增多同时保留正常红细胞生成的途径。中央该提案的目标是描述驱动 EpoR 的依赖机制应激性红细胞生成和 JAK2(V617F) 驱动的红细胞增多症中的 sCFU-E 扩增。目标 1 确定 sCFU-E 扩展中的机制和 EpoR 信号传导。目标2 利用我们新的 RNA-seq 数据来检查 EpoR 下游的新型调节因子应激性红细胞生成、鼠红细胞增多症和人真性红细胞增多症。一起，这些结果将阐明控制应激红细胞生成的机制和病理性红细胞增多症，并可能导致新的治疗干预措施。