In this competitive renewal application of the Program Program grant >30 yrs in existence, diverse approaches are used to address the singular theme of gene regulation in developing red blood cells. The Project Leaders are united in their commitment to the developing red cell as an experimental system in which to make fundamental biological discoveries that will inform our understanding of cell differentiation and directly impact our capacity to treat disorders of the red cell, including congenital and acquired anemias. The Program encompasses the most relevant vertebrate systems (human, mouse, and zebrafish) and employs contemporary genetic approaches, including gene modification using CRISPR/cas9 and innovative genetic screens. Deep, longstanding, and intensive interactions and collaborations among the Project Leaders ensures synergy in the accomplishment of the proposed goals of the research. Project 1 (S.H. Orkin, Project Leader) builds on prior groundbreaking work on the role of BCL11A in HbF repression and centers on the interaction of BCL11A and other transcription factors with the nuclear matrix, the turnover of BCL11A protein and the search for small molecules that destabilize the protein in erythroid cells, and cis-regulatory sites of BCL11A-binding in the human ?-globin cluster. In Project 2, H. Lodish (Project Leader) and his colleagues focus on the pathways by which self-renewal of red cell progenitors is controlled. Project 3 (L. Zon, Project Leader) addresses the role of transcription elongation in red cell gene expression and its intersections with signaling pathways. In Project 4 (D.E. Bauer, Project Leader), erythroid cell super-enhancer elements will be analyzed functionally with innovative CRISPR/cas9 saturating mutagenesis, an approach recently pioneered in the Program. In Project 5 (B. Paw, Project Leader), new genes/proteins involved in iron and heme metabolism will be characterized for their physiological roles in mouse/human/zebrafish systems. Each of the projects in this Program grant addresses critical aspects of the expression program and function of erythroid cells. These studies are founded on the premise that discoveries emerging from the proposed projects will provide new opportunities for the design of novel approaches to the understanding and management of red blood cell disorders, including the hemoglobinopathies (sickle cell disease and ?-thalassemia), other congenital anemias, and acquired conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL032262-35A1
Application #
9276315
Study Section
Special Emphasis Panel (HLBP (JH))
Program Officer
Qasba, Pankaj
Project Start
1997-07-01
Project End
2022-03-31
Budget Start
2017-04-16
Budget End
2018-03-31
Support Year
35
Fiscal Year
2017
Total Cost
$2,033,175
Indirect Cost
$555,572
Name
Boston Children's Hospital
Department
Type
Independent Hospitals
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Canver, Matthew C; Orkin, Stuart H (2016) Customizing the genome as therapy for the β-hemoglobinopathies. Blood 127:2536-45
Gao, Xiaofei; Lee, Hsiang-Ying; da Rocha, Edroaldo Lummertz et al. (2016) TGF-β inhibitors stimulate red blood cell production by enhancing self-renewal of BFU-E erythroid progenitors. Blood 128:2637-2641
Shi, Jiahai; Yuan, Bingbing; Hu, Wenqian et al. (2016) JAK2 V617F stimulates proliferation of erythropoietin-dependent erythroid progenitors and delays their differentiation by activating Stat1 and other nonerythroid signaling pathways. Exp Hematol 44:1044-1058.e5
Hagedorn, Elliott J; Cillis, Jennifer L; Curley, Caitlyn R et al. (2016) Generation of Parabiotic Zebrafish Embryos by Surgical Fusion of Developing Blastulae. J Vis Exp :
Yien, Yvette Y; Paw, Barry H (2016) A role for iron deficiency in dopaminergic neurodegeneration. Proc Natl Acad Sci U S A 113:3417-8
Nasrallah, Rabab; Fast, Eva M; Solaimani, Parham et al. (2016) Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes. Blood 128:1928-1939
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CHARGE Consortium Hematology Working Group (2016) Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits. Nat Genet 48:867-76
Gao, Xin; Wu, Tongyu; Johnson, Kirby D et al. (2016) GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis. Stem Cell Reports 6:368-82

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