Abstract
Many acute and chronic anemias are not treatable with erythropoietin (Epo) because the terminal erythroid progenitors (CFU-Es) that respond to Epo are too few in number to maintain sufficient red blood cell production. Treatment of these anemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of these Epo-sensitive CFU-E progenitors. Glucocorticoids, used clinically to treat such anemias despite major side effects, increase erythroid output by expanding the number of early committed progenitor cells, but the underlying molecular mechanisms were unknown.
Several years ago, the speaker showed that glucocorticoids specifically stimulate self-renewal divisions of the earliest committed erythroid progenitor, the burst-forming unit erythroid (BFU-E), leading over time to an increase in numbers of CFU-Es and subsequently terminally differentiated red cells. He went on to demonstrate that activation of the peroxisome proliferator-activated receptor alpha (PPARα) by climactically tested PPARα agonists, used for dyslipidemia, synergizes with the glucocorticoid receptor to promote BFU-E cell expansion and over time these agonists synergize to greatly increase production of both human and mouse red blood cells. In BFU-E progenitors PPARα co-occupies many chromatin sites with the glucocorticoid receptor and stimulates transcription of an overlapping set of genes that are essential for self-renewal divisions. His discovery of the role of PPARα agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPARα agonists he used may improve the efficacy of corticosteroids in treating Epo resistant anemias.
About the speaker
Prof Harvey F Lodish received his PhD in genetics from the Rockefeller University in 1966. He joined the Department of Biology at Massachusetts Institute of Technology in 1968 and is currently a Professor of Biology and Biomedical Engineering. He was also a founding member of the new Whitehead Institute for Biomedical Research.
Prof Lodish’s research focuses on biomechanics, biomolecular engineering, drug delivery, macromolecular biochemistry, and tissue engineering. He isolated, cloned, and characterized numerous proteins and noncoding RNAs that play key roles in the formation of blood and fat cells and that regulate metabolism of glucose and fatty acids. His results have important implications for the treatment of anemias, cancer, diabetes, heart disease and obesity.
Prof Lodish was elected a fellow of the American Academy of Arts and Sciences (1999), a member of the US National Academy of Sciences (1987) and a fellow of the American Association for the Advancement of Science (1986). He also received the Sandra K Masur Senior Leadership Award by the American Society for Cell Biology (2017) and the Pioneer Award by the Diamond Blackfan Anemia Foundation (2016).
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