MEMBRANE DYNAMICS IN NORMAL AND ABNORMAL ERYTHROID CELLS

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Plasma membranes of both mature and differentiating erythroid cells are dynamic structures that respond to changes in the intracellular and extracellular environment. This proposal uses time resolved laser and video microscopy techniques, including fluorescence photobleaching recovery, polarized fluorescence depletion, quantitative fluorescence imaging, and nanovid microscopy, to study the molecular mechanisms that regulate cell surface receptor mobility and distribution in human red blood cell, erythroblast, reticulocyte, and erythroleukemia cell membranes and in models of erythroid differentiation including urine erythroleukemia cells and murine erythroblasts and reticulocytes. We investigate the roles of specific binding interactions, steric hindrance interactions, complex formation, and aggregate formation in controlling the mobility and distribution of the major red cell transmembrane proteins, band 3 and glycophorin A. We study the molecular basis for the removal of senescent red cells from the circulation, focusing on the roles of band 3 aggregation, surface immunoglobulin deposition, and translocation of phosphatidylserine from the inner to the outer leaflet of the red cell membrane. We examine the plasma membrane mechanisms that control the mobility and distribution of transferrin receptors and fibronectin receptors in erythroleukemia cells and developing erythroid cells in culture, the influence of receptor occupancy by ligand on these processes, and the mutual interactions between erythroid cell differentiation and regulation of receptor dynamics and expression. The long term goal of this research is to understand, in molecular detail, the forces that regulate the mobility and distribution of transmembrane proteins and lipids in erythroid cell membranes, the relationship between derangements in these regulatory mechanisms and the pathophysiology of disease in abnormal membrane states, and the relationship between alterations in these control mechanisms and the cellular physiology of erythroid cell development.