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Hypoxia 2009 Speakers
Joe Prchal
University of Utah, Salt Lake City, UT
Email: josef.prchal@hsc.utah.edu
Talk Title: Genetic mechanisms underlying regulation of hemoglobin mass
Session: New Thoughts about Globins
Abstract: Hemoglobin, the sole carrier of oxygen supply to the tissues, accounts for most cytoplasmic protein of an erythrocyte. The erythrocyte is an enucleated cell lacking protein synthesizing machinery with limited energy metabolism. Thus, genetic mechanisms resulting in decreased hemoglobin; i.e. anemia could be due to mutations of a) membrane lipids and cytoskeleton, b) enzymes of glycolytic pathway, pentose shunt, glutathione synthesis and reduction, and those scavenging nucleotide remains, c) hemoglobin synthesis that include globin, heme, and iron supply and defects of iron transport, and lastly e) disordered production or increased destruction of erythrocytes. In contrast, the parameters determining an increased hemoglobin mass; i.e. polycythemia or erythrocytosis are due to germ line or somatic mutations of a) the enzyme synthesizing 2,3 BPG, a metabolic intermediate which regulates hemoglobin-oxygen affinity and thus oxygen delivery, b) specific mutations of a or b globin genes that increase hemoglobin-oxygen affinity and thus decrease oxygen delivery, and c) increase production of erythrocytes. In this review we will concentrate on polycythemias. Polycythemias can be either primary polycythemias that are caused by inherited or acquired somatic mutations affecting the hematopoietic progenitors, leading to excessive erythropoiesis. In contrast, in secondary polycythemia normal progenitors are acted on by external factors present in increased concentration, most commonly erythropoietin (Epo). Secondary polycythemias may overstimulate erythropoiesis in excess of the physiological needs “inappropriate polycythemias," or appropriately in response to a hypoxic stimulus “appropriate polycythemia." Most polycythemias are acquired, but both primary and secondary polycythemias may be inherited. In this review we will discuss the genetic heterogeneity of individual responses to hypoxia, and also discuss the current understanding of molecular basis of organismus in response to hypoxia and its inherited disturbance as exemplified by Chuvash polycythemia.

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