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：
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
项目类别：
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

项目摘要

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。再生或“应激红细胞生成”以从贫血中恢复，红细胞生成进一步增加。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，基础红细胞生成和应激红细胞生成的潜在机制仍不清楚。促红细胞生成素 (Epo) 及其受体 EpoR 与 EpoR 结合可激活相关的酪氨酸激酶。 JAK2，启动下游信号传导，导致红系细胞的存活、增殖和分化。虽然主要研究了分化程度较高的红系前体细胞中的 EpoR 信号传导，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，是 Epo 的唯一目标。 SCFU-E 在红细胞应激中扩张，并且对于红细胞的恢复至关重要。初步研究表明，激活 JAK2 突变体 JAK2(V617F) 可驱动骨髓增生性肿瘤中的红细胞增多。研究中，我们发现 scFU-E 增殖和分化涉及新的 Epo/EpoR 信号传导。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 Epo 还诱导 SLC23A2（一种抗坏血酸（维生素 C））的表达。 scFU-E 中的转运蛋白会积累高水平的抗坏血酸，而抗坏血酸会加速 sCFU-E 的形成。该提案的目的是阐明夜曲素和抗坏血酸的驱动机制。目标 1 将在应激性红细胞生成和红细胞增多的情况下促进 sCFU-E 的增殖和分化。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 分化将决定 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。