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 健康成人通过基础红细胞生成过程每秒产生200万个红细胞。 红细胞生成不足导致贫血，这是一个重要的全球人类健康问题。期间 为了从贫血中恢复，红细胞生成进一步增加。应力 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，其基本机制仍不清楚。基础和应激红细胞生成均受 促红细胞生成素（Epo）及其受体EpoR。Epo与EpoR结合激活相关的酪氨酸激酶 JAK 2，其启动下游信号传导，导致红系细胞的存活、增殖和分化。 虽然已经广泛研究了更分化的红系前体中的EpoR信号传导， 在早期的祖先中还没有被阐明。 这一建议是基于我们最近发现的一个以前未被承认的早期集落形成的人口， 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 在红系细胞应激中扩增，并且对于红系细胞的恢复至关重要。sCFU-E也被 激活JAK 2突变体JAK 2（V617 F），以驱动骨髓增生性肿瘤中的红细胞增多。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NADP（H）磷酸酶，调节细胞氧化 应激促进sCFU-E增殖。Epo还诱导SLC 23 A2的表达，SLC 23 A2是一种抗坏血酸盐（维生素C） 转运蛋白，在sCFU-E中。sCFU-E积累高水平的抗坏血酸，抗坏血酸促进sCFU-E 分化该提案的目标是阐明夜曲素和抗坏血酸驱动细胞凋亡的机制。 在应激红细胞生成和红细胞增多的情况下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将阐明潜在的机制 抗坏血酸依赖性sCFU-E分化。目的3将确定Nocturnin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红细胞生成的机制， 红细胞增多症，并可能导致新的治疗干预贫血和那些可以靶向 红细胞增多，同时保持基础红细胞生成。