Over the last several years our group and others produces and characterized transgenic mice, that synthesize Hb S or other polymerizing hemoglobin variants as animal models of sickle cell disease. However, none of the mice are ideal models of sickle cell disease. owing to the persistence of mouse hemoglobins or the synthesis of variants which have different properties from those of authentic Hb S. Recent success in application of gene-knockout technology has generate mice that synthesize human sickle and fetal hemoglobins exclusively. The transgenic Hb S-F mice to be anemic with reticulocytosis and 10% irreversibly sickled cells. Preliminary results show the Hb S-F mice to be anemic with reticulocytosis and 10% irreversibly sickled cells. Our overall goal is to use the Hb S-F mice to examine pathologic changes and evaluate therapeutic agents in vivo. Our first specific aim is to characterize the Hb S-F mice over time. We will examine structural and functional aspects of all major organ systems and hematological parameters under ambient conditions to establish baseline data for comparison with experimental interventions of hypoxic stress or treatment with therapeutic agents. Our second specific aim is to use these mice to study the mechanism of initiation of vaso-occlusion. As a new tool to study such mechanisms we will determine the percentage of partially oxygenated sickled cells (POSC), a new type of sickled cells found in the circulating blood of patients as recently described by the applicants. Since POSC contain various amounts of Hb S fibers and undergo sickling without a delay time upon exposure to hypoxia they may contribute to the initiation of vaso-occlusive crises. We will determine the percentage and morphologic changes of POSC in venous and arterial blood before, during and after exposure of Hb S-F mice to various levels of hypoxia. Our third specific aim is to study the affect of Hb F-inducing agents, such as hydroxyurea, butyrate, or erythropoietin, on the percentage of Hb F and F cells using Hb S-F mice. Our fourth specific aim is to evaluate the combined use of hydroxyurea and other agents using the Hb S-F mice. Since the new Hb S-F mice produce human gamma-globin they present a unique opportunity to evaluate the combined effects of therapeutic agents that induce gamma-globin synthesis and agents that inhibit Hb S polymerization by other mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Comprehensive Center (P60)
Project #
2P60HL038632-11
Application #
6272782
Study Section
Project Start
1998-04-24
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ballas, Samir K; Connes, Philippe; Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (2018) Rheological properties of sickle erythrocytes in patients with sickle-cell anemia: The effect of hydroxyurea, fetal hemoglobin, and ?-thalassemia. Eur J Haematol 101:798-803
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Adachi, Kazuhiko; Ding, Min; Asakura, Toshio et al. (2009) Relationship between beta4 hydrogen bond and beta6 hydrophobic interactions during aggregate, fiber or crystal formation in oversaturated solutions of hemoglobin A and S. Arch Biochem Biophys 481:137-44
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Uematsu, Hidemasa; Takahashi, Masaya; Hatabu, Hiroto et al. (2007) Changes in T1 and T2 observed in brain magnetic resonance imaging with delivery of high concentrations of oxygen. J Comput Assist Tomogr 31:662-5
Obata, Kazuo; Mattiello, Julian; Asakura, Kenji et al. (2006) Exposure of blood from patients with sickle cell disease to air changes the morphological, oxygen-binding, and sickling properties of sickled erythrocytes. Am J Hematol 81:26-35
Akbar, Mohammed G K; Tamura, Yutaka; Ding, Min et al. (2006) Inhibition of hemoglobin S polymerization in vitro by a novel 15-mer EF-helix beta73 histidine-containing peptide. Biochemistry 45:8358-67
Adachi, Kazuhiko; Ding, Min; Surrey, Saul et al. (2006) The Hb A variant (beta73 Asp-->Leu) disrupts Hb S polymerization by a novel mechanism. J Mol Biol 362:528-38
Asakura, Toshio; Asakura, Kenji; Obata, Kazuo et al. (2005) Blood samples collected under venous oxygen pressure from patients with sickle cell disease contain a significant number of a new type of reversibly sickled cells: constancy of the percentage of sickled cells in individual patients during steady state. Am J Hematol 80:249-56

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