The symptoms of the major hemoglobinopathies are related to 1) the primary inherited defect in hemoglobin synthesis; 2) physicochemical instability of the hemoglobin or of its component parts; and 3) iron overload coming either from transfusions or from the disease itself. Our objective is to seek basic information about the pathogenesis of these symptoms, with major emphasis on the genetic control of hemoglobin synthesis. We are currently investigating the role of cyclic-nucleotide dependent protein kinases in the control of globin synthesis. Our studies are conducted in reticulocyte cell free systems. The rabbit is used as a standard species for studies of hemoglobin synthesis, while sheep possessing the gene for Hb A are an ideal model for the study of genetic control; they undergo a reversible change in hemoglobin type in response to anemia. Newborn calves, human cord blood, and patients with hemoglobinopathy are sources of reticulocytes for studies of fetal and adult hemoglobin synthesis. Our previous observations of molecular differences between the ferritins of erythroblasts and reticuloendothelial cells is also being used as the basis for investigation of the metabolic interrelationships of these two distinct iron storage pools with the major objective of defining their individual roles in the etiology of secondary hemochromotosis. We currently hypothesize that a "natural" antibody to autologous ferritin plays a significant part in the transport of erythroid cell ferritin to reticuloendothelial cells. Experiments will be designed to test this hypothesis, and to assess its potential pathophysiologic importance.