Regulation of human erythropoiesis

项目摘要 我们在这个项目中的目的是阐明调节红细胞生成机制的复杂性， 伙计我们认为，由于红系细胞的发育在不同的发育阶段是不同的，因此迫切需要进行这种研究。 与大多数其他细胞不同的关键方面，目前的知识主要依赖于这些方面。红细胞生成是 一个独特的过程，因为每次有丝分裂产生的子细胞，在形态和功能上， 与它们的母细胞不同。这有直接的临床意义，因为红细胞生成障碍， 几种贫血包括Diamond-Blackfan贫血（DBA）和骨髓增生异常综合征（MDS 红细胞分化的阶段特异性缺陷。在拟议的研究中，我们将集中研究其中两项 红细胞分化的最重要方面，即调节红细胞分化的机制基础， 祖细胞生成和终末红细胞分化，包括去核。为了完成这些 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，是以特异性基因表达变化为特征的异质细胞群 模式.解决这一问题将是理解这些疾病的分子基础的重要一步。 DBA中的红细胞生成障碍是由于DBA中的红细胞发育缺陷出现在祖细胞阶段。 我们的第二个目标是探索在肿瘤细胞中调节抗凋亡基因表达的多种机制。 多染性和正染性成红细胞以及随后诱导有丝分裂/胞质分裂基因 允许正染性成红细胞去核。我们假设，基因表达的失调， 这些发育阶段负责MDS中终末分化细胞的凋亡。我们 预计拟议研究的成功完成将为正常的 红系细胞发育以及与红细胞生成紊乱相关的疾病。识别 近年来，与红细胞生成异常相关的疾病越来越多， 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.