Hemoglobinopathies including sickle cell disease (SCD) and ?-thalassemia are the most common genetic disorders in the United States. SCD patients benefit from fetal hemoglobin (HbF;?2?2) induction to ameliorate clinical symptoms, decrease mortality and prolonged survival and quality of life. Treatment options for SCD are insufficient because therapeutic approaches to correct nitric oxide depletion and endothelium dysfunction attempted and failed at reversing the downstream negative effects of SCD. The FDA approved Hydroxyurea therapy was HbF inducing along with anti-inflammatory properties;unfortunately, Hydroxyurea is effective in only half of SCD patients. A critical barrier to progres in developing new and additional effective treatment options for SCD are gaps in knowledge and understanding of molecular mechanisms involved in ?-globin gene regulation. Our goal is to design novel molecular treatment strategies for SCD by beginning to address the gap in knowledge and understanding of molecular mechanisms involved in ?-globin gene regulation. Our central hypothesis is that alteration in stage-specific DNA-binding protein motifs mediated by heritable genetic mutations, produced chromatin modifications conducive to persistent HbF expression after birth. Our approach to the problem is built upon knowledge gleaned from naturally occurring mutations producing hereditary persistence of HbF (HPFH) expression phenotypes. Our objectives are to 1) determine the genomic interplay among known enhancers and a newly identified fetal chromatin domain and novel DNA- binding proteins in ?-globin regulation during human hemoglobin switching;and 2) discover plasma protein biomarkers and inherited genetic modifiers associated with HPFH in SCD. Our expected outcomes include: 1) development of molecular strategies for HbF induction for the treatment of SCD;2) generation of experimental data to fill knowledge gaps about ?-globin regulation;3) discovering novel plasma protein biomarkers and inherited genetic modifiers associated with HPFH in SCD that can act as an in vitro predictive surrogate of response to HbF inducing agents. Our impact on SCD medicine will include 1) creation of a new paradigm of molecular mechanisms involved in globin gene regulation during development;2) characterization of a novel fetal chromatin domain and its interaction with other known regulatory regions and 3) discovery of transcription factors that can be targeted for therapeutic intervention.
Aim 1 will test the hypothesis there exist a fetal chromatin domain involved in ?-globin regulation during erythropoiesis.
Aim 2 will test the hypothesis that plasma proteins associated with HPFH are expressed at different levels in SCD and that transcription factors mediating HPFH have altered expression to modulate HbF production.
Aim 3 will test the hypothesis that KLF1 activates negative transcriptional regulators of ?-globin expression during fetal erythropoiesis.
|Zhu, Xingguo; Li, Biaoru; Pace, Betty S (2017) NRF2 mediates ?-globin gene regulation and fetal hemoglobin induction in human erythroid progenitors. Haematologica 102:e285-e288|
|Ward, Christina M; Li, Biaoru; Pace, Betty S (2016) Original Research: Stable expression of miR-34a mediates fetal hemoglobin induction in K562 cells. Exp Biol Med (Maywood) 241:719-29|
|Pace, Betty S; Liu, Li; Li, Biaoru et al. (2015) Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease. Exp Biol Med (Maywood) 240:1050-64|
|Perrine, Susan P; Pace, Betty S; Faller, Douglas V (2014) Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am 28:233-48|
|Peterson, Kenneth R; Costa, Flávia C; Fedosyuk, Halyna et al. (2014) A cell-based high-throughput screen for novel chemical inducers of fetal hemoglobin for treatment of hemoglobinopathies. PLoS One 9:e107006|
|Li, Biaoru; Ding, Lianghao; Yang, Chinrang et al. (2014) Characterization of transcription factor networks involved in umbilical cord blood CD34+ stem cells-derived erythropoiesis. PLoS One 9:e107133|
|Promsote, Wanwisa; Makala, Levi; Li, Biaoru et al. (2014) Monomethylfumarate induces ?-globin expression and fetal hemoglobin production in cultured human retinal pigment epithelial (RPE) and erythroid cells, and in intact retina. Invest Ophthalmol Vis Sci 55:5382-93|
|Liu, Li; Karmakar, Subhradip; Dhar, Ruby et al. (2013) Regulation of G?-globin gene by ATF2 and its associated proteins through the cAMP-response element. PLoS One 8:e78253|
|Li, Biaoru; Ding, Lianghao; Li, Wei et al. (2012) Characterization of the transcriptome profiles related to globin gene switching during in vitro erythroid maturation. BMC Genomics 13:153|
|Ramakrishnan, Valya; Pace, Betty S (2011) Regulation of ýý-globin gene expression involves signaling through the p38 MAPK/CREB1 pathway. Blood Cells Mol Dis 47:12-22|
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