The regulation of human globin gene expression is a critical problem in human hematopoiesis. An understanding of this regulation could lead to new approaches to the treatment of hereditary disorders of human hemoglobin including sickle cell anemia and the thalassemias. Recent studies indicate that multiple genetic elements within and flanking the globin genes are involved in the tissue-specific and developmental regulation of these genes. The current proposal will extend our ongoing studies of the cis acting elements within and surrounding the gamma, delta, and beta globin genes regulating the expression of these genes, and the trans acting factors in erythroid cells whose interactions with these cis acting elements are responsible for their regulated expression. More specifically, the goals of these studies are: 1) To define in more detail the cis acting elements within or surrounding the gamma, delta, and beta genes by characterizing new natural (inherited) mutations and by the in vitro construction of hybrid and mutant genes. We will continue to analyze the effect of these mutations after gene transfer into embryonic-fetal (K562), fetal-adult human (KMOE), mouse erythroleukemia (MEL), and nonerythroid cells. 2) To continue to study the role of trans acting factors in erythroid cells that regulate the expression of the epsilon, gamma, delta, and beta globin genes. In these studies, we will attempt to isolate and characterize these factors from various erythroid and nonerythroid cell lines at different stages of development. Characterization of these specific regulatory factors could lead to their cloning and to their use in stimulating gamma globin production in human erythroid cells, a potential approach to the treatment of beta thalassemia and sickle cell anemia. In addition, these experiments may increase our understanding of the processes regulating the switch from gamma globin to beta globin synthesis that occurs in late fetal life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK025274-26
Application #
3483444
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1978-09-01
Project End
1993-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
26
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Zhang, Zhi; Mahajan, Sajan; Zhang, Xiaochung et al. (2003) Tumor necrosis factor alpha is a key mediator of gut inflammation seen in amebic colitis in human intestine in the SCID mouse-human intestinal xenograft model of disease. Infect Immun 71:5355-9
O'Neill, D W; Schoetz, S S; Lopez, R A et al. (2000) An ikaros-containing chromatin-remodeling complex in adult-type erythroid cells. Mol Cell Biol 20:7572-82
Qin, S; Ward, M; Raftopoulos, H et al. (1999) Competitive repopulation of retrovirally transduced haemopoietic stem cells. Br J Haematol 107:162-8
Xue, H; O'Neill, D; Wang, X et al. (1999) HemT-3, an alternative transcript of mouse gene HemT specific to male germ cells. Gene 240:193-9
O'Neill, D; Yang, J; Erdjument-Bromage, H et al. (1999) Tissue-specific and developmental stage-specific DNA binding by a mammalian SWI/SNF complex associated with human fetal-to-adult globin gene switching. Proc Natl Acad Sci U S A 96:349-54
Kaubisch, A; Ward, M; Schoetz, S et al. (1999) Up-regulation of amphotrophic retroviral receptor expression in human peripheral blood CD34+ cells. Am J Hematol 61:243-53
Raftopoulos, H; Ward, M; Bank, A (1998) High-level transfer and long-term expression of the human beta-globin gene in a mouse transplant model. Ann N Y Acad Sci 850:178-90
Raftopoulos, H; Ward, M; Leboulch, P et al. (1997) Long-term transfer and expression of the human beta-globin gene in a mouse transplant model. Blood 90:3414-22
Caruso, M; Bank, A (1997) Efficient retroviral gene transfer of a Tat-regulated herpes simplex virus thymidine kinase gene for HIV gene therapy. Virus Res 52:133-43
Flamm, M; Bornschlegel, K; Wu, S et al. (1996) Expression of a cosmid containing the LCR, (A)gamma, delta, and beta globin genes in mouse erythroleukemia cells. Am J Hematol 53:181-7

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