Although health disparities between racial and ethnic populations have been acknowledged for a variety of systemic diseases, minority health also has been negatively impacted by genetic disorders that are prevalent among minority groups. Sickle cell disease (SCD) is a devastating genetic disorder worldwide. SCD is also associated with serious complications such as stroke and hypertension. Hydroxyurea (HU) was introduced for the treatment of this disorder with the morbidity and mortality of SCD patients significantly improving, which is attributable at least in part to an increased production of fetal hemoglobin (Hb F) by HU. However, one third to half of SCD patients are resistant to this chemical and they demonstrate no significant increase in Hb F levels. The mechanisms of action of HU as well as those underlying resistance to HU therapy still remain unclear. The long-term goal of this proposal is to improve health conditions of African-Americans by developing novel HU-based combination therapies for SCD patients. In this proposal, we will test the hypothesis that HU-induced Hb F expression is enhanced by combining a cAMP-dependent phosphodiesterase inhibitor.
In Specific Aim 1, we will determine intracellular signaling pathways that play a critical role in HU-induced Hb F expression. Using CD34+-derived primary erythroid cells, we will examine whether HU modulates the activities of intracellular signaling pathways that have been shown to be involved in Hb F expression.
Specific Aim 2 is to determine whether HU-induced Hb F expression is further increased by combining a cAMP-dependent PDE inhibitor. Here we will utilize SCD model mice, which exclusively express human globins including beta S globin. SCD mice will allow us to confirm the role of cAMP signaling pathways in Hb F expression as well as to provide an experimental arena to develop novel HU-based combination therapies for SCD patients. If successfully implemented, this proposal will enhance our understanding of mechanisms that regulate the expression of the g-globin genes during development and provide important information to develop novel Hb F inducers for treating beta-globin disorders, which are also common to minority populations.
Development of new treatment modalities for anemic disorders that are distributed worldwide should contribute to reducing the medical care costs that are required for the palliative therapies of these anemic diseases, eventually resulting in a contribution to general public health and welfare.
|Ikuta, Tohru; Sellak, Hassan; Odo, Nadine et al. (2016) Nitric Oxide-cGMP Signaling Stimulates Erythropoiesis through Multiple Lineage-Specific Transcription Factors: Clinical Implications and a Novel Target for Erythropoiesis. PLoS One 11:e0144561|
|Piel, FrÃ©dÃ©ric B; Adamkiewicz, Thomas V; Amendah, Djesika et al. (2016) Observed and expected frequencies of structural hemoglobin variants in newborn screening surveys in Africa and the Middle East: deviations from Hardy-Weinberg equilibrium. Genet Med 18:265-74|
|Anea, Ciprian B; Lyon, Matthew; Lee, Itia A et al. (2016) Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease. Am J Hematol 91:173-8|
|Jaja, Cheedy; Bowman, Latanya; Wells, Leigh et al. (2015) Preemptive Genotyping of CYP2C8 and CYP2C9 Allelic Variants Involved in NSAIDs Metabolism for Sickle Cell Disease Pain Management. Clin Transl Sci 8:272-80|
|Baker, Charlotte; Grant, Althea M; George, Mary G et al. (2015) Contribution of Sickle Cell Disease to the Pediatric Stroke Burden Among Hospital Discharges of African-Americans-United States, 1997-2012. Pediatr Blood Cancer 62:2076-81|
|Jaja, Cheedy; Patel, Niren; Scott, Stuart A et al. (2014) CYP2C9 allelic variants and frequencies in a pediatric sickle cell disease cohort: implications for NSAIDs pharmacotherapy. Clin Transl Sci 7:396-401|
|Gutsaeva, Diana R; Montero-Huerta, Pedro; Parkerson, James B et al. (2014) Molecular mechanisms underlying synergistic adhesion of sickle red blood cells by hypoxia and low nitric oxide bioavailability. Blood 123:1917-26|
|Ghoshal, Pushpankur; Rajendran, Mythilypriya; Odo, Nadine et al. (2014) Glycosylation inhibitors efficiently inhibit P-selectin-mediated cell adhesion to endothelial cells. PLoS One 9:e99363|
|Ikuta, Tohru; Kuroyanagi, Yuichi; Odo, Nadine et al. (2013) A common signaling pathway is activated in erythroid cells expressing high levels of fetal hemoglobin: a potential role for cAMP-elevating agents in Î²-globin disorders. J Blood Med 4:149-59|
|Zhu, Xingguo; Wang, Yongchao; Pi, Wenhu et al. (2012) NF-Y recruits both transcription activator and repressor to modulate tissue- and developmental stage-specific expression of human Î³-globin gene. PLoS One 7:e47175|
Showing the most recent 10 out of 17 publications