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.

项目概要 健康成年人通过基础红细胞生成过程每秒产生 200 万个红细胞。 红细胞生成不足会导致贫血，这是一个严重的全球人类健康问题。期间 再生或“应激性红细胞生成”以从贫血中恢复，红细胞生成进一步增加。压力 红细胞生成对于手术、化疗、骨髓移植和感染的恢复至关重要； 然而，其根本机制仍不清楚。基础红细胞生成和应激红细胞生成均受调节 促红细胞生成素（Epo）及其受体EpoR。 Epo 与 EpoR 结合可激活相关酪氨酸激酶 JAK2，启动下游信号传导，导致红系细胞的存活、增殖和分化。 虽然更多分化的红系前体细胞中的 EpoR 信号传导已被广泛研究，但 EpoR 信号传导 在早期祖细胞中的作用尚未阐明。 该提议基于我们最近对先前未被识别的早期群体形成群体的发现 红系祖细胞 (CFU-E)，我们将其命名为应激 CFU-E 或 sCFU-E。 sCFU-E 是 Epo 的靶标，仅 在红细胞应激下扩张，对于红细胞的恢复至关重要。 scFU-E 也被劫持 激活 JAK2 突变体 JAK2(V617F)，以驱动骨髓增生性肿瘤中的红细胞增多。在初步 研究中，我们发现 scFU-E 增殖和分化涉及新的 Epo/EpoR 信号传导。我们 发现 Epo 诱导 Nocturnin 的表达，Nocturnin 是一种调节细胞氧化的 NADP(H) 磷酸酶 应激促进 scFU-E 增殖。 Epo 还诱导 SLC23A2（一种抗坏血酸（维生素 C））的表达 转运蛋白，以 scFU-E 为单位。 sCFU-E 积累高水平的抗坏血酸，抗坏血酸加速 sCFU-E 差异化。该提案的目标是阐明夜曲素和抗坏血酸驱动的机制 应激红细胞生成和红细胞增多背景下 sCFU-E 的增殖和分化。目标1将 确定抗坏血酸输入对 sCFU-E 功能的作用。目标 2 将阐明潜在机制 抗坏血酸依赖性 sCFU-E 分化。目标 3 将确定夜曲素和氧化应激的作用 scFU-E 增殖中的信号传导。这些结果将阐明控制应激性红细胞生成和 红细胞增多症，并可能导致针对贫血症和靶向治疗的新治疗干预措施 红细胞增多，同时保留基础红细胞生成。