Regulation of human erythropoiesis

项目摘要 我们在这个项目中的目的是阐明调控红细胞生成的机制的复杂性。 天哪。我们认为迫切需要这样的研究，因为红系细胞的发育在 与大多数其他细胞的关键方面不同，目前的知识很大程度上依赖于这些细胞。红细胞生成是一种 每个有丝分裂产生形态和功能相同的子细胞的独特过程 与它们的父代细胞截然不同。这有直接的临床意义，因为红细胞生成紊乱，这是 几种贫血，包括钻石-布莱克凡贫血(DBA)和骨髓增生异常综合征(MDS)结果 来自红系分化的阶段特异性缺陷。在建议的研究中，我们会集中研究其中两项 红系分化最重要的方面，即调节红系的机制基础 祖细胞的产生和红系终末分化，包括去核。为了实现这些目标 目标方面，我们提出了两个具体目标。在第一个目标中，我们假设红系祖细胞BFU-E 和CFU-E是以特定基因表达变化为特征的异质细胞群体 模式。解决这个问题将是理解分子基础的重要一步。 DBA的红系发育异常是由于DBA的红系发育缺陷出现在祖细胞阶段。 我们的第二个目标将探索多种调控抗凋亡基因表达的机制。 多染红细胞和正染红细胞与随后有丝分裂/胞质分裂基因的诱导 允许去核正染红细胞。我们假设，放松对基因表达的管制 这些发育阶段与MDS终末分化细胞的凋亡有关。我们 预计拟议研究的成功完成将为正常 红系细胞发育以及转化为与红细胞生成紊乱相关的疾病。认同感 近年来，越来越多的疾病与红细胞生成异常有关，这增加了新的紧迫性 鉴于缺乏有效的治疗方法，继续进行拟议的研究。我们希望并期待 我们提出的研究方向可能为开发新的治疗策略奠定基础。

Project Summary Our purpose in this project is to illuminate the complexities of the mechanisms regulating erythropoiesis in man. We believe that there is a pressing need for such a study since erythroid cell development differs in critical respects from that of most other cells, on which current knowledge largely rests. Erythropoiesis is a distinctive process in that each mitosis generates daughter cells that are morphologically and functionally distinct from their parent cell. This has a direct clinical bearing since disordered erythropoiesis, a feature of several anemias including Diamond-Blackfan Anemia (DBA) and myelodysplastic syndromes (MDS) result from stage specific defects in erythroid differentiation. In the proposed studies, we will focus on two of the most important aspects of erythroid differentiation, namely the mechanistic bases regulating erythroid progenitor generation and terminal erythroid differentiation including enucleation. In order to accomplish these objectives, we propose two specific aims. In the first aim we hypothesize that erythroid progenitors, BFU-E and CFU-E, are heterogeneous cell populations characterized by changes in specific gene expression patterns. Resolving this question will be an essential step towards understanding the molecular basis for disordered erythropoiesis in DBA as erythroid developmental defects in DBA arise at the progenitor stage. Our second aim will explore the multifarious mechanisms regulating the expression of anti-apoptotic genes in polychromatic and orthochromatic erythroblasts and the subsequent induction of mitosis/cytokinesis genes allowing enucleation of orthochromatic erythroblasts. We hypothesize that deregulation of gene expression at these developmental stages are responsible for apoptosis of terminally differentiating cells in MDS. We anticipate that successful accomplishment of the proposed studies will provide novel insights into normal erythroid cell development as well as into diseases associated with disordered erythropoiesis. The recognition in recent years of an increasing number of conditions linked to anomalies of erythropoiesis, lend new urgency to pursue the proposed studies in view of the paucity of effective treatments. We hope and expect that the research direction we propose may lay the groundwork for developing novel therapeutic strategies.