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.
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