The proposed project plans to study several metabolic, biosynthetic and membrane transport functions of erythroid precursor cells in sideroblastic anemia and erythroleukemia. It is our hypothesis that the characteristic disturbance in hemoglobin synthesis is due to an abnormality in the cellular uptake and transport of iron affecting in particular cells. Increased membrane permeability for iron would lead to its excessive deposition in mitochondria thereby leading to impaired metabolic and biosynthetic functions of this organelle and to increased synthesis of ferritin which would be in competition with that of globin. Furthermore a comparative study of the energy metabolism and (lactic) acid production of erythroid precursors in these conditions offers a unique opportunity to test one of the current hypothesis of tumor growth, which stipulates that persistent alteration of intracellular pH leads to loss of regulatory mechanisms in the cell. Utilizing both suspensions and explants of bone marrow we propose to examine in erythroid cells (purified by a combination of passage through glass wool columns and centrifugation through linear albumin gradients): 1) Uptake and transport of iron across plasma and mitochondrial membranes, 2) Rate of de novo synthesis of ferritin and hemoglobin, 3) Metabolic fate of delta-aminolevulinate and, 4) Studies on energy metabolism. From these investigations we hope to define the pathogenetic mechanism of the disturbed hemoglobin synthesis and establish whether sideroblastic anemia and erythroleukemia are causally related. The therapeutic effectiveness of iron chelators and pyridoxine administration will be also assessed by in vitro experiments.
NIH ExPorter
NIH ExPorter