We hypothesize that in sickle cell anemia, the source of hemodynamic abnormalities is not only abnormal red cell rheology (sickling and adhesion to endothelium), but a derangement of microvascular controls secondary to endothelial dysfunction. This proposal focuses on two potential modulators of microvascular flow and vasoocclusion in sickle cell anemia. First, endothelial dysfunction in response to hypoxia, mechanical injury (red cell sickling and adhesion), and oxidative stress (secondary to transient ischemic episodes) would affect the ability of microvasculature to respond to rheological challenge. Second, abnormal adherence of red cells to vascular endothelium would not only result in endothelial injury, but also in a prosickling environment. The objective of this revised proposal is to examine the relationship between abnormal rheology, oxidative stress and vascular tone under in vivo conditions in the sickle context, using transgenic and knockout sickle mouse lines. We will test the following specific hypotheses: 1) Test the hypothesis that sickling and attendant flow abnormalities (e.g., transient vasoocclusive events) will cause oxidative stress, microvascular injury and vascular tone abnormalities. To test this hypothesis, we will investigate the effect of enhanced sickling (hypoxia), examine the effect of arginine supplementation, and evaluate the effect of selected anti-oxidants; 2) Test the hypothesis that genetic and experimental modulations of red cell density and polymer formation will impact endothelium and thereby microvascular function. To test this aspect, we will determine the effects of anti-sickling fetal hemoglobin and experimental modulations of red cell density; 3) Test the hypothesis that red cell adhesion in vivo not only contributes to endothelial injury but plays a crucial role in microvascular obstruction. To test this hypothesis, we will focus on the role of endothelial activation, specific adhesion molecules, hypoxia, NO, anti-oxidants, and use DNA microarray technology to identify genes regulated by adhesion inducing factors. The proposed research involves participation of scientists with expertise in microcirculation, hematology, biochemistry, cell biology and molecular biology. These studies are expected to elucidate new mechanisms with relevance to human sickle cell disease and with potential therapeutic implications. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070047-03
Application #
6878529
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Evans, Gregory
Project Start
2003-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$334,000
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Chen, Qiuying; Fabry, Mary E; Rybicki, Anne C et al. (2012) A transgenic mouse model expressing exclusively human hemoglobin E: indications of a mild oxidative stress. Blood Cells Mol Dis 48:91-101
Barabino, Gilda A; Platt, Manu O; Kaul, Dhananjay K (2010) Sickle cell biomechanics. Annu Rev Biomed Eng 12:345-67
Dasgupta, Trisha; Fabry, Mary E; Kaul, Dhananjay K (2010) Antisickling property of fetal hemoglobin enhances nitric oxide bioavailability and ameliorates organ oxidative stress in transgenic-knockout sickle mice. Am J Physiol Regul Integr Comp Physiol 298:R394-402
Kaul, Dhananjay K; Finnegan, Eileen; Barabino, Gilda A (2009) Sickle red cell-endothelium interactions. Microcirculation 16:97-111
Kaul, Dhananjay K; Zhang, Xiaoqin; Dasgupta, Trisha et al. (2008) Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilators, hemolysis, and oxidative stress. Am J Physiol Heart Circ Physiol 295:H39-47
Kaul, D K (2008) Sickle red cell adhesion: many issues and some answers. Transfus Clin Biol 15:51-5
Finnegan, Eileen M; Barabino, Gilda A; Liu, Xiao-du et al. (2007) Small-molecule cyclic alpha V beta 3 antagonists inhibit sickle red cell adhesion to vascular endothelium and vasoocclusion. Am J Physiol Heart Circ Physiol 293:H1038-45
Kaul, Dhananjay K; Liu, Xiao-du; Zhang, Xiaoqin et al. (2006) Inhibition of sickle red cell adhesion and vasoocclusion in the microcirculation by antioxidants. Am J Physiol Heart Circ Physiol 291:H167-75
Kaul, Dhananjay K; Liu, Xiao-du; Zhang, Xiaoqin et al. (2006) Peptides based on alphaV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation. Am J Physiol Cell Physiol 291:C922-30
Dasgupta, Trisha; Hebbel, Robert P; Kaul, Dhananjay K (2006) Protective effect of arginine on oxidative stress in transgenic sickle mouse models. Free Radic Biol Med 41:1771-80

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