Our goal is acquisition of basic information on the cell biology of mammalian hemoglobin ontogeny. A clinical goal is to utilize this information in ultimately divising attempts to ameliorate certain human hemoglobinopathies by manipulating ontogenic mechanisms. During ontogeny, synthesis of embryonic globin chains is replaced by synthesis of adult globin chains. Although earlier investigators relegated synthesis of embryonic globin to yolk-sac erythroid cells and synthesis of adult globin to ontogenically later sites (liver, spleen, bone marrow), recent work has established co-synthesis of embryonic and adult globins in yolk-sac erythroid cells of hamster, mouse, and human. Our studies will use hamster as the primary source of cells, but will utilize mouse for comparative purposes. Assays of globin-chain synthesis in hamster yolk-sac erythroid cells show that globin ontogeny (embryonic to adult) is nearly completed during the time span (approximately six days) in which the only circulating erythroid cell is derived from the yolk-sac. These actively replicating primitive erythroid cells from colonies in culture, and changes in chain synthesis in culture closely resemble the ontogeny of chain synthesis in vivo. We intend to utilize this physiologic cell system in approaching our two specific aims.
Our first aim i s to determine the extent to which an apparent pre-programming of the globin-chain ontogenic process can be diverted. We shall be assaying effects of diverse environmental influences: hormones, conditioned media, and certain non-physiologic chemical agents, all reported to affect globin-gene expression in other cell systems. The second specific aim is to search for cell mechanisms underlying our observation that colony growth and globin-chain ontogeny can proceed in culture only when both erythropoietin and thyroid hormone are present. With these aims as introductory probes into mechanisms, we anticipate that the ability to exercise tight experimental control in culture will facilitate useful interpretation of results.
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