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.
Abnormal production of red cells due to ineffective erythropoiesis is a feature of a large number of human hematological disorders including Cooley's anemia, congenital dyserythropoieticanemia (CDA), Diamond- Blackfan Anemia (DBA), and various bone marrow failure syndromes such as myelodysplastic syndrome (MDS). This research project proposes to develop improved understanding of red cell production in normal and diseased states. It is anticipated that the findings from the proposed studies will lead to a better understanding of erythroid cell development and differentiation in health and disease and provide insights into disordered red cell production in a number of human red cell disorders that are a major global health problem.
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