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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Exploratory Grants (P20)
Project #
5P20MD003383-05
Application #
8410046
Study Section
Special Emphasis Panel (ZRG1-EMNR-L)
Project Start
2013-01-16
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$104,374
Indirect Cost
$25,361
Name
Georgia Regents University
Department
Type
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Ikuta, Tohru; Thatte, Hemant S; Tang, Jay X et al. (2011) Nitric oxide reduces sickle hemoglobin polymerization: potential role of nitric oxide-induced charge alteration in depolymerization. Arch Biochem Biophys 510:53-61
Gutsaeva, Diana R; Parkerson, James B; Yerigenahally, Shobha D et al. (2011) Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood 117:727-35
Ikuta, Tohru; Adekile, Adekunle D; Gutsaeva, Diana R et al. (2011) The proinflammatory cytokine GM-CSF downregulates fetal hemoglobin expression by attenuating the cAMP-dependent pathway in sickle cell disease. Blood Cells Mol Dis 47:235-42