The proposed research will focus on vaso-occlusive mechanisms in sickle cell anemia, emphasizing the role of erthrocytic and vascular factors. In particular, a better understanding of the integrated physiology in vivo mechanisms is required to devise effective therapies. The overall hypothesis is that in sickle cell anemia, reversible sickling in vivo results in pleiotropic effects such as red cell heterogeneity, endothelial injury, red cell-endothelial interactions, and altered vascular responses. These abnormalities will then contribute to vasoocclusive crisis and multiple organ damage. The Applicant will use a transgenic mouse model expressing human, alpha, betaS, betaS- Antilles globins on the mouse homozygous Beta-major deletional background. This model meets the basic requirements necessary to test the above hypothesis, such as the presence of red cell heterogeneity, intravascular sickling, red cell adhesion and chronic, multiple organ damage. In vivo studies in the sickle transgenic mouse will be complemented by selected experiments with human SS cells in ex vivo systems. In the transgenic mouse, they will test the hypothesis that the above pathological manifestations are a direct consequence of intravascular sickling. The proposed in vivo studies will elucidate: i) microrheologic correlates of microvascular abnormalities; ii) the role of cytokinase and NO; iii) and mechanisms of altered microvascular responses. The proposed experiments with human SS cells are driven by our novel findings that show involvement of band 3 protein in adhesion using ex vivo mesocecum vasculature as well as human endothelial cells in a flow chamber. The results of these studies are expected to elucidate new mechanisms with relevance to the human sickle cell disease, particularly in validating the basis for certain therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045931-07
Application #
2415575
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1990-09-30
Project End
2000-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Kaul, Dhananjay K; Fabry, Mary E (2004) In vivo studies of sickle red blood cells. Microcirculation 11:153-65
Kaul, D K; Liu, X; Nagel, R L (2001) Ameliorating effects of fluorocarbon emulsion on sickle red blood cell-induced obstruction in an ex vivo vasculature. Blood 98:3128-31
Kaul, D K; Liu, X D; Fabry, M E et al. (2000) Impaired nitric oxide-mediated vasodilation in transgenic sickle mouse. Am J Physiol Heart Circ Physiol 278:H1799-806
Kaul, D K; Tsai, H M; Liu, X D et al. (2000) Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood 95:368-74
Kaul, D K; Liu, X D (1999) Rate of deoxygenation modulates rheologic behavior of sickle red blood cells at a given mean corpuscular hemoglobin concentration. Clin Hemorheol Microcirc 21:125-35
Barabino, G A; Liu, X D; Ewenstein, B M et al. (1999) Anionic polysaccharides inhibit adhesion of sickle erythrocytes to the vascular endothelium and result in improved hemodynamic behavior. Blood 93:1422-9
Kaul, D K; Liu, X D; Nagel, R L et al. (1998) Microvascular hemodynamics and in vivo evidence for the role of intercellular adhesion molecule-1 in the sequestration of infected red blood cells in a mouse model of lethal malaria. Am J Trop Med Hyg 58:240-7
Hirsch, R E; Jelicks, L A; Wittenberg, B A et al. (1997) A first evaluation of the natural high molecular weight polymeric Lumbricus terrestris hemoglobin as an oxygen carrier. Artif Cells Blood Substit Immobil Biotechnol 25:429-44
Kaul, D K; Fabry, M E; Costantini, F et al. (1995) In vivo demonstration of red cell-endothelial interaction, sickling and altered microvascular response to oxygen in the sickle transgenic mouse. J Clin Invest 96:2845-53
Kaul, D K; Chen, D; Zhan, J (1994) Adhesion of sickle cells to vascular endothelium is critically dependent on changes in density and shape of the cells. Blood 83:3006-17

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