Role of EPO in terminal erythroid maturation

EPO 在终末红细胞成熟中的作用

• 批准号: 8417125
• 负责人: James Palis
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417125
• 关键词: Adult; Anemia; Apoptosis; Apoptotic; Blood Circulation; Bone Marrow; CFU-E; Cell Lineage; Cell Maturation; Cells; Defect; EPOR gene; Embryo; Embryonic Development; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Fetal Liver; Flow Cytometry; Gene Expression; Genes; Goals; Growth; Hormones; Image; Immunophenotyping; In Vitro; Kinetics; Knowledge; Lead; Malignant - descriptor; Medicare; Mitochondria; Modeling; Molecular; Mus; Nuclear; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physical condensation; Play; Process; Production; Proteins; RNA; Radiation Injuries; Red Cell Mass result; Regulation; Research; Role; Signal Transduction; Staging; System; Testing; Transcript; Yolk Sac; abstracting; cytokine; in vivo; innovation; insight; mouse model; mutant; novel; postnatal; prevent; progenitor; receptor

DESCRIPTION (provided by applicant): The overall aim of this proposal is to better understand the cellular and molecular underpinnings of terminal erythroid cell maturation. Our red cell mass is sustained by a robust process of cell maturation that is primarily dependent on the hormone erythropoietin (EPO). EPO, signaling through its cognate receptor (EPOR) provides a critical survival signal to late-stage definitive erythroid progenitors making it difficult to study its role in the downstream terminal maturation o erythroid precursors. While EPO is widely recognized to be essential for definitive erythropoiesis, its role in primitive erythropoiesis, a transient lineage necessary for embryonic growth and survival, remains controversial and poorly understood. We hypothesize that EPO plays a central role in the terminal maturation of the primitive erythroid lineage. This hypothesis will be tested in Aim 1 studies by delineating the role of EPO in mouse embryos lacking EPOR as well as in an ex vivo 2-step primitive erythroid culture system. Our recent studies of radiation injury to the bone marrow have led us to hypothesize that terminal erythroid cell maturation is characterized by a transition from a pro-apoptotic to an anti-apoptotic state (Peslak, 2011). Preliminary studies indicate that EPO prevents the apoptosis of late-stage primitive erythroid precursors. The persistence of mutant primitive erythroid cells in EPOR-null embryos provides a unique opportunity to investigate the role of EPO in terminal stages of erythroid cell maturation. We have identified pro- and anti-apoptotic genes whose levels are dramatically altered by loss of EPO. In Aim 2, we will more fully characterize the expression of pro- and anti-apoptotic genes in wild-type and EPOR-null erythroblasts. Furthermore, we will delineate the role of Stat signaling in the regulation of Bcl-xL both in wild- type and in mutant primitive erythroblasts lacking Stat5 signaling. Our studies of EPO function in late stages of erythroid maturation may ultimately provide insights, by comparison, into the role of this clinically important cytokine in EPO-responsive non-erythroid cells, both normal and malignant. (End of Abstract)

描述（由申请人提供）： 该建议的总体目的是更好地了解末端红细胞成熟的细胞和分子基础。我们的红细胞肿块是通过鲁棒的细胞成熟过程来维持的，该过程主要取决于激素促红细胞生成素（EPO）。 EPO通过其同源受体（EPOR）信号传导为晚期确定的红细胞祖细胞提供了关键的存活信号，因此很难研究其在下游末端成熟e红红色前体中的作用。尽管EPO被广泛认为对于确定的红细胞生成至关重要，但其在原始红细胞生成中的作用是胚胎生长和生存所必需的短暂谱系，仍然有争议且知名度不佳。我们假设EPO在原始红细胞谱系的末端成熟中起着核心作用。这个假设 将通过描述EPO在缺乏EPOR的小鼠胚胎中以及在Vivo 2步基原始的红细胞培养系统中的小鼠胚胎中的作用来对AIM 1研究进行测试。我们最近的辐射研究 骨髓的损伤使我们假设末端红细胞成熟的特征是从促凋亡到抗凋亡状态的过渡（Peslak，2011）。初步研究表明，EPO阻止了晚期原始红细胞前体的凋亡。 Epor-null胚胎中突变原始红细胞细胞的持久性为研究EPO在红细胞成熟的末端阶段的作用提供了独特的机会。我们已经确定了促凋亡基因，其水平会因EPO丢失而发生巨大变化。在AIM 2中，我们将更充分地表征野生型和null红细胞中促凋亡基因的表达。此外，我们将描述STAT信号在野生型和突变原始的原始红细胞中缺乏STAT5信号传导的bcl-XL调节中的作用。相比之下，我们对红系成熟后期的EPO功能的研究最终可以提供洞察力，以使这种临床上重要的细胞因子在正常和恶性肿瘤的EPO响应性非果皮细胞中的作用。 （抽象的结尾）