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: 10658667
• 负责人: LILY JUNSHEN HUANG
• 金额: $ 41万
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658667
• 关键词: Acceleration; Acetylcysteine; Adult; Affect; Anemia; Antioxidants; Ascorbic Acid; BFU-E; Binding; Blood Substitutes; Bone Marrow Transplantation; CD34 gene; CFU-E; Cell Culture Techniques; Cell Cycle; Cell division; Cells; Cellular Stress; DNA; Development; Dioxygenases; Erythrocytes; Erythrocytoses; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Etiology; Exhibits; Funding; Goals; Growth; Health; Hematologic Neoplasms; Human; Impairment; In Vitro; Infection; JAK2 gene; Knockout Mice; Length; Mediating; Mediator; Molecular; Mus; Myeloproliferative disease; NADP; Names; Natural regeneration; Operative Surgical Procedures; Oxidative Stress; Pathogenicity; Pathologic; Persons; Phosphoric Monoester Hydrolases; Polycythemia; Population; Process; Production; Proliferating; Protein Tyrosine Kinase; Reactive Oxygen Species; Receptor Signaling; Recovery; Role; Signal Transduction; Stress; System; Testing; Therapeutic Agents; Translating; Work; alpha ketoglutarate; ascorbate; biological adaptation to stress; chemotherapy; cofactor; demethylation; design; effective therapy; epigenome; erythroid differentiation; improved; knock-down; mutant; nocturnin; novel; novel therapeutic intervention; novel therapeutics; preservation; progenitor; receptor; response; sodium DEPENDENDENT vitamin C transporter 1

PROJECT SUMMARY Healthy adults produce 2 million erythrocytes every second through the process of basal erythropoiesis. Insufficient erythrocyte production causes anemia, which is a significant global human health problem. During regeneration or “stress erythropoiesis” to recover from anemia, erythrocyte production further increases. Stress erythropoiesis is critical for recovery from surgery, chemotherapy, bone marrow transplantation and infection; however, the underlying mechanisms remain unclear. Both basal and stress erythropoiesis are regulated by erythropoietin (Epo) and its receptor EpoR. Epo binding to the EpoR activates the associated tyrosine kinase JAK2, which initiate downstream signaling leading to survival, proliferation and differentiation of erythroid cells. While EpoR signaling in more differentiated erythroid precursors has been extensively studied, EpoR signaling in early progenitors has not been elucidated. This proposal is based on our recent findings of a previously unrecognized population of early colony-forming erythroid progenitors (CFU-E), which we named stress CFU-E or sCFU-E. sCFU-E are targets of Epo, are only expanded in erythroid stress, and are essential for recovery of the erythron. sCFU-E are also hijacked by the activating JAK2 mutant, JAK2(V617F), to drive erythrocytosis in myeloproliferative neoplasms. In preliminary studies, we discovered that sCFU-E proliferation and differentiation involve novel Epo/EpoR signaling. We found that Epo induces expression of Nocturnin, a NADP(H) phosphatase that regulates cellular oxidative stress to promote sCFU-E proliferation. Epo also induces expression of SLC23A2, an ascorbate (Vitamin C) transporter, in sCFU-E. sCFU-E accumulates high levels of ascorbate, and ascorbate accelerates sCFU-E differentiation. The goal of this proposal is to elucidate the mechanism by which Nocturnin and ascorbate drive proliferation and differentiation of sCFU-E in the context of stress erythropoiesis and erythrocytosis. Aim 1 will determine the role of ascorbate import on sCFU-E function. Aim 2 will elucidate mechanisms underlying ascorbate-dependent sCFU-E differentiation. Aim 3 will determine the role of Nocturnin and oxidative stress signaling in sCFU-E proliferation. These results will elucidate mechanisms controlling stress erythropoiesis and erythrocytosis, and may lead to novel therapeutic interventions for anemia and those that can target erythrocytosis while preserving basal erythropoiesis.

项目摘要 健康的成年人每秒在基本的红细胞生成过程中每秒产生200万个红细胞。 红细胞生产不足会导致贫血，这是一个重大的全球人类健康问题。期间 从贫血中恢复的再生或“压力红细胞生成”，红细胞的产生进一步增加。压力 红细胞生成对于从手术，化学疗法，骨髓移植和感染中恢复至关重要。 但是，基本机制尚不清楚。碱性和压力红细胞生成都受 促红细胞生成素（EPO）及其受体Epor。 EPO与EPOR的结合激活相关的酪氨酸激酶 JAK2启动下游信号传导，导致红细胞细胞的生存，增殖和分化。 虽然更分化的红细胞前体中的EPOR信号已被广泛研究，但Epor信号传导 在早期祖细胞中尚未阐明。 该提案是基于我们最近对先前未识别的早期菌落形成人群的发现 红细胞祖细胞（CFU-E），我们将其命名为应力CFU-E或SCFU-E。 SCFU-E是EPO的目标，仅是 在红细胞胁迫下扩展，对于恢复厄尔特龙至关重要。 SCFU-E也被 激活JAK2突变体JAK2（V617F），以在骨髓增生性肿瘤中驱动红细胞增多。在初步 研究，我们发现SCFU-E增殖和分化涉及新颖的EPO/Epor信号传导。我们 发现EPO诱导了调节细胞氧化物的NADP（H）磷酸酶的夜曲蛋白的表达 压力促进SCFU-E增殖。 EPO还影响抗坏血酸盐（维生素C）SLC23A2的表达 转运蛋白，在SCFU-E中。 SCFU-E积累了高水平的抗坏血酸盐，抗坏血酸会加速SCFU-E 分化。该提议的目的是阐明夜生蛋白和抗坏血酸驱动器的机制 在压力红细胞生成和红细胞增多症的背景下，SCFU-E的增殖和分化。目标1意志 确定进口抗坏血酸在SCFU-E函数上的作用。 AIM 2将阐明基础机制 抗坏血酸依赖性的SCFU-E分化。 AIM 3将确定夜生蛋白和氧化应激的作用 SCFU-E增殖中的信号传导。这些结果将阐明控制压力红细胞生成的机制和 红细胞增多症，可能导致贫血的新型热干预措施 促红细胞增多症，同时保存基本的红细胞生成。