The overall goal of our research is to delineate the mechanism which controls HbF production in man and to use this information for the therapeutic induction of HbF in patients with beta chain hemoglobinopathies.
Our specific aims are: 1) To investigate the cellular mechanism of HbF formation in the adult and its relationship to the process of differentiation of erythroid progenitors. Specifically we will: a) Produce acute perturbations of erythropoiesis in primates and test how the kinetic changes affect the globin programs of erythroid progenitors and precursors. b) Use recombinant erythropoietin as a means of perturbing the kinetics of normal and anemic erythropoiesis and examine effects on progenitor cells and their HbF programs. Test whether administration of recombinant Epo results in sustained stimulation of F-cells in animals and in patients with HbS disease. c) Investigate the relationship between F-cell formation and intrinsic anomalies of erythroid cell differentiation. d) Attempt to delineate the relationship between beta locus haplotypes and induction of HbF in response to stress. e) Investigate mechanisms of HbF induction by cell cycle-specific drugs. f) Investigate the nature and the mechanism of action of humoral factors which induce or inhibit HbF production in BFUe cultures. Purify, biochemically characterize, and attempt to clone the HbF inducer. 2) To investigate the mechanisms of globin gene switching during ontogeny. Specifically: a) Search for heterospecific trans acting inducers of gamma gene expression. b) Develop a system allowing molecular analysis of trans regulation of human globin gene expression. c) Using this system, clone the genes of trans acting elements which control the expression of globin genes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL020899-14
Application #
3485712
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1977-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
14
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Cao, Hua; Stamatoyannopoulos, George (2006) Histone deacetylase inhibitor FK228 is a potent inducer of human fetal hemoglobin. Am J Hematol 81:981-3
Migliaccio, Giovanni; Di Baldassarre, Angela; Di Rico, Cristina et al. (2005) Spontaneous switch from Agamma- to beta-globin promoter activity in a stable transfected dual reporter vector. Blood Cells Mol Dis 34:174-80
Cao, Hua; Jung, Manfred; Stamatoyannopoulos, George (2005) Hydroxamide derivatives of short-chain fatty acid have erythropoietic activity and induce gamma gene expression in vivo. Exp Hematol 33:1443-9
Asano, Haruhiko; Murate, Takashi; Naoe, Tomoki et al. (2004) Molecular cloning and characterization of ZFF29: a protein containing a unique Cys2His2 zinc-finger motif. Biochem J 384:647-53
Li, Qiliang; Fang, Xiangdong; Han, Hemei et al. (2004) The minimal promoter plays a major role in silencing of the galago gamma-globin gene in adult erythropoiesis. Proc Natl Acad Sci U S A 101:8096-101
Cao, Hua (2004) Pharmacological induction of fetal hemoglobin synthesis using histone deacetylase inhibitors. Hematology 9:223-33
Skarpidi, Evangelia; Cao, Hua; Heltweg, Birgit et al. (2003) Hydroxamide derivatives of short-chain fatty acids are potent inducers of human fetal globin gene expression. Exp Hematol 31:197-203
Swank, Richard A; Skarpidi, Eva; Papayannopoulou, Thalia et al. (2003) The histone deacetylase inhibitor, trichostatin A, reactivates the developmentally silenced gamma globin expression in somatic cell hybrids and induces gamma gene expression in adult BFUe cultures. Blood Cells Mol Dis 30:254-7
Liakopoulou, Effie; Li, Qiliang; Stamatoyannopoulos, George (2002) Induction of fetal hemoglobin by propionic and butyric acid derivatives: correlations between chemical structure and potency of Hb F induction. Blood Cells Mol Dis 29:48-56
Navas, Patrick A; Li, Qiliang; Peterson, Kenneth R et al. (2002) Activation of the beta-like globin genes in transgenic mice is dependent on the presence of the beta-locus control region. Hum Mol Genet 11:893-903

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