The hemoglobinopathies comprise the most prevalent class of human genetic diseases. Those involving the a-globin locus include a-thalassemia and sickle cell disease (SCD). A variety of observations and experimental results indicate that strategies designed to increase levels of fetal hemoglobin in the erythrocytes of people with these diseases will produce significant clinical benefits. However, none of the currently available strategies offer the combination of safety, efficacy and convenience of use that would make them applicable to most patients worldwide. Recent success in the development of targeted pharmacologic agents for the treatment of a wide variety of human cancers attests to the ability of this approach to produce drugs with improved efficacy and decreased side effects. This strategy has the potential to produce more effective agents for the pharmacologic induction of HbF. A prerequisite for the rational development of such drugs is a thorough knowledge of the pathways involved in the regulation of HbF production. Despite more than three decades of research, the underlying molecular mechanisms that regulate a-globin gene expression and HbF production during adult erythroid differentiation and in response to HbF inducing agents remain poorly understood. Based on progress made during the previous funding period of this project we have published a novel mechanistic theory, based on cell stress signaling, to explain the action of fetal Hb inducing agents. If correct, this model will unify most HbF inducing agents under a common mechanism of action and will provide new molecular targets and an overall framework for the development of improved agents for HbF induction. In this application, we propose an experimental plan to test our hypothesis and to begin to pre-clinical development of more effective HbF inducing drugs for people with SCD and a-thalassemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073442-06
Application #
7851236
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Qasba, Pankaj
Project Start
2009-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$393,447
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Hahn, Cynthia K; Lowrey, Christopher H (2014) Induction of fetal hemoglobin through enhanced translation efficiency of ?-globin mRNA. Blood 124:2730-4
Schaeffer, Emily K; West, Rachel J; Conine, Sarah J et al. (2014) Multiple physical stresses induce ?-globin gene expression and fetal hemoglobin production in erythroid cells. Blood Cells Mol Dis 52:214-24
Hahn, Cynthia K; Lowrey, Christopher H (2013) Eukaryotic initiation factor 2? phosphorylation mediates fetal hemoglobin induction through a post-transcriptional mechanism. Blood 122:477-85
Macari, Elizabeth R; Schaeffer, Emily K; West, Rachel J et al. (2013) Simvastatin and t-butylhydroquinone suppress KLF1 and BCL11A gene expression and additively increase fetal hemoglobin in primary human erythroid cells. Blood 121:830-9
Macari, Elizabeth R; Lowrey, Christopher H (2011) Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway. Blood 117:5987-97
Boosalis, Michael S; Castaneda, Serguei A; Trudel, Marie et al. (2011) Novel therapeutic candidates, identified by molecular modeling, induce ?-globin gene expression in vivo. Blood Cells Mol Dis 47:107-16
Lathrop, Melissa J; Hsu, Mei; Richardson, Christine A et al. (2009) Developmentally regulated extended domains of DNA hypomethylation encompass highly transcribed genes of the human beta-globin locus. Exp Hematol 37:807-813.e2
Hsu, Mei; Richardson, Christine A; Olivier, Emmanuel et al. (2009) Complex developmental patterns of histone modifications associated with the human beta-globin switch in primary cells. Exp Hematol 37:799-806.e4
Mabaera, Rodwell; West, Rachel J; Conine, Sarah J et al. (2008) A cell stress signaling model of fetal hemoglobin induction: what doesn't kill red blood cells may make them stronger. Exp Hematol 36:1057-72
Mabaera, Rodwell; Greene, Michael R; Richardson, Christine A et al. (2008) Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin. Blood 111:411-20

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