Role of EPO in terminal erythroid maturation

EPO 在终末红细胞成熟中的作用

• 批准号: 8875051
• 负责人: James Palis
• 金额: $ 37.8万
• 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/8875051
• 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）：

项目成果

Extensively self-renewing erythroblasts derived from transgenic β-yac mice is a novel model system for studying globin switching and erythroid maturation.

• DOI: 10.1016/j.exphem.2014.03.006
• 发表时间: 2014-07
• 期刊: Experimental hematology
• 影响因子: 2.6
• 作者: Getman M;England SJ;Malik J;Peterson K;Palis J;Steiner LA
• 通讯作者: Steiner LA

Primitive and definitive erythropoiesis in mammals.

哺乳动物中的原始和确定性红细胞生成。

• DOI: 10.3389/fphys.2014.00003
• 发表时间: 2014
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Palis J