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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Kafina, Martin D; Paw, Barry H (2017) Intracellular iron and heme trafficking and metabolism in developing erythroblasts. Metallomics 9:1193-1203
Doulatov, Sergei; Vo, Linda T; Macari, Elizabeth R et al. (2017) Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors. Sci Transl Med 9:
Seguin, Alexandra; Takahashi-Makise, Naoko; Yien, Yvette Y et al. (2017) Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes. J Biol Chem 292:16284-16299
Grillo, Anthony S; SantaMaria, Anna M; Kafina, Martin D et al. (2017) Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals. Science 356:608-616
Yien, Yvette Y; Ducamp, Sarah; van der Vorm, Lisa N et al. (2017) Mutation in human CLPX elevates levels of ?-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria. Proc Natl Acad Sci U S A 114:E8045-E8052
Gao, Xiaofei; Lee, Hsiang-Ying; Li, Wenbo et al. (2017) Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation. Proc Natl Acad Sci U S A 114:10107-10112
Perlin, Julie R; Robertson, Anne L; Zon, Leonard I (2017) Efforts to enhance blood stem cell engraftment: Recent insights from zebrafish hematopoiesis. J Exp Med 214:2817-2827
Perlin, Julie R; Sporrij, Audrey; Zon, Leonard I (2017) Blood on the tracks: hematopoietic stem cell-endothelial cell interactions in homing and engraftment. J Mol Med (Berl) 95:809-819
van Rooij, Frank J A; Qayyum, Rehan; Smith, Albert V et al. (2017) Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. Am J Hum Genet 100:51-63

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