In man, hemoglobin (Hb) production switches from fetal (alpha2-gamma2) to adult (alpha2-beta-2) during ontogeny. This switch is reversed in hematologic stress. Manipulation offers therapeutic potential in sickle cell disease and thalassemia. The mouse model proposed here may provide understanding of this switching mechanism. In strains with major and minor Hbs, the proportion of minor Hb decreases during ontogeny, and may increase during hematopoietic stress. Studies of in vivo conditions which lead to increased minor Hb, and of the types of erythroid progenitors which are present in normal or stress hematopoiesis, may indicate factors which modulate Hb synthesis. Friend murine erythroleukemia cells (ELC) also produce Hb; the minor/major ratio depends on the cell line and the inducing agent. Subclones of ELC produce Hbs in ratios specific to each clone. We will investigate Hb regulation at the clonal level. Murine erythroid cells may be fused with human erythroid or non-erythroid cells, to investigate Hb regulation in mixed environments. All of the work in this proposal is designed to indicate the efficacy of the murine model for studies of Hb switching, and to investigate Hb regulation at the cellular level.
