In this competitive renewal application of this Program Project grant now in its 30th year, multicjisciplinary approaches are employed to address the central theme of gene regulation in developing red blood cells. The premise underlying this work is that progress in the fundamental biology ofthe erythroid cell will provide critical, new knowledge that will have a positive impact on the management ofthe major red cell disorders, ncluding the hemoglobin disorders (sickle cell anemia and p-thalassemia), as well as congenital and acquired anemias. The Program utilizes multiple vertebrate systems (mouse, zebrafish, and human), contemporary genetics and cell biology, and emerging high-throughput chemical and shRNA screening procedures. Extensive interaction between the Project Leaders ensures intellectual vitality and synergy in execution of the proposed studies. The current proposals rest on exciting recent advances by the Project Leaders. In Project 1 (H. Lodish, Project Leader) new transcription factors, RNA polymerase II elongation factors, and chromatin-modifying enzymes important for terminal red cell development will be characterized. In Project 2 (S. Orkin, Project Leader) strategies will be developed to translate recent break-though findings in the study of fetal hemoglobin switching in humans to effective platforms for the discovery of new pathways or drugs suitable for directed reactivation of HbF in adult with hemoglobin disorders. In Project 3 (L. Zon, Project Leader) a newly discovered aspect of erythroid cell gene expression, transcriptional elongation, will be explored further in both the mouse and zebrafish through the study of conditional mutant mice and the role ofthe HEXIM complex in erythroid development. In Project 4 (A. Cantor, Project Leader) molecular approaches will be utilized to delineate the determinants that distinguish gene activation versus repression for the master erythroid factor GATA-1 during erythroid cell maturation. In Project 5 (B. Paw, Project Leader) new components ofthe complexes required for proper iron and heme trafficking in developing red cells will be characterized in both the zebrafish and mouse. Each ofthe Projects in this Program Project grant addresses important aspects of the expression program and function of erythroid cells Findings from these studies will provide new opportunities for the design of novel approaches to the management of red blood cell disorders.
This project is directly relevant to the major hemoglobin disorders (sickle cell anemia and thalassemia) because new methods for reactivation of HbF expression would revolutionize treatment for these conditions. The unmet need is enormous and of global proportions, and estimated to grow in the coming years. The deliverables from our research are new approaches to treatment.
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|Ludwig, Leif S; Gazda, Hanna T; Eng, Jennifer C et al. (2014) Altered translation of GATA1 in Diamond-Blackfan anemia. Nat Med 20:748-53|
|Chen, Cynthia; Lodish, Harvey F (2014) Global analysis of induced transcription factors and cofactors identifies Tfdp2 as an essential coregulator during terminal erythropoiesis. Exp Hematol 42:464-76.e5|
|Hagedorn, Elliott J; Durand, Ellen M; Fast, Eva M et al. (2014) Getting more for your marrow: boosting hematopoietic stem cell numbers with PGE2. Exp Cell Res 329:220-6|
|Yien, Yvette Y; Robledo, Raymond F; Schultz, Iman J et al. (2014) TMEM14C is required for erythroid mitochondrial heme metabolism. J Clin Invest 124:4294-304|
|Cheng, Albert W; Shi, Jiahai; Wong, Piu et al. (2014) Muscleblind-like 1 (Mbnl1) regulates pre-mRNA alternative splicing during terminal erythropoiesis. Blood 124:598-610|
|Shmukler, Boris E; Reimold, Fabian R; Heneghan, John F et al. (2014) Molecular cloning and functional characterization of zebrafish Slc4a3/Ae3 anion exchanger. Pflugers Arch 466:1605-18|
|Hu, Wenqian; Yuan, Bingbing; Lodish, Harvey F (2014) Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation. Dev Cell 30:660-72|
|Chung, Jacky; Anderson, Sheila A; Gwynn, Babette et al. (2014) Iron regulatory protein-1 protects against mitoferrin-1-deficient porphyria. J Biol Chem 289:7835-43|
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