This project proposes to answer question about the molecular basis of the pathology engendered by HbC and its effect on double heterozygotes for HbC and HbS. The first fundamental question is: what is the molecular basis of the tendency of oxyHb to crystallize? The present data points to the combination of the presence of the Beta6lysine mutation and alteration of the central cavity of the BetaA helix moving away from the heme as the best candidates. With state-of-the- art spectroscopy and X-ray crystallography the investigators propose to prove or disprove this hypothesis. The next fundamental question is: are these modulators in red cells that favor or inhibit crystallization, but the question remains whether or not other components of the cytosol are participants. To answer this question the investigators need to know more about crystal growth and more about the presence or absence of coring in these crystals. The investigators have joined forces with Rosenberger and Vekilov (Center for Microgravity and Materials Research, University of Alabama) to answer this question, using cutting-age custom made instrumentation to follow crystal growth and coring (coring is the presence of """"""""impurities that accelerate or retard crystal growth). Finally, another fundamental question is the molecular basis of the uniform microcytosis which varies among the syndromes containing HbC. One possibility is that this effect is related to abnormal interaction of HbC with the membrane specifically affecting volume-regulating transporters. Hence, the investigators need to test if the abnormal turn-off of K:C1 co- transport, discover by the group in C cells, is the culprit. For this purpose the investigators are in the process of generating transgenic mice expressing HbC and transgenic mice expressing the human K:C1 co- transporter (since the mouse K:C1 co-transporter has phenomenological differences with the human transporter). The potential answers to the above questions have practical applications: since SC disease is caused by an increase in intracellular HB concentration induced by HbC in RBC containing only 50 percent of Hbs, the investigations could cure this disease by correcting the transport abnormality. Also, since crystallization of HbC has polymerization in SC cells, the severity of the syndrome will be reduced significantly.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Comprehensive Center (P60)
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Albert Einstein College of Medicine
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Olivier, Emmanuel N; Rybicki, Anne C; Bouhassira, Eric E (2006) Differentiation of human embryonic stem cells into bipotent mesenchymal stem cells. Stem Cells 24:1914-22
Srinivasulu, Sonati; Perumalsamy, Krishnaveni; Upadhya, Rajendra et al. (2006) Pair-wise interactions of polymerization inhibitory contact site mutations of hemoglobin-S. Protein J 25:503-16
Oh, Il-Hoan; Fabry, Mary E; Humphries, R Keith et al. (2004) Expression of an anti-sickling beta-globin in human erythroblasts derived from retrovirally transduced primitive normal and sickle cell disease hematopoietic cells. Exp Hematol 32:461-9
Kaul, Dhananjay K; Liu, Xiao-du; Chang, Hee-Yoon et al. (2004) Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice. J Clin Invest 114:1136-45
Kaul, Dhananjay K; Fabry, Mary E (2004) In vivo studies of sickle red blood cells. Microcirculation 11:153-65
Romero, Jose R; Suzuka, Sandra M; Nagel, Ronald L et al. (2004) Expression of HbC and HbS, but not HbA, results in activation of K-Cl cotransport activity in transgenic mouse red cells. Blood 103:2384-90
Wang, Jian-Ying; Drlica, Karl (2003) Modeling hybridization kinetics. Math Biosci 183:37-47
Alami, Raouf; Fan, Yuhong; Pack, Stephanie et al. (2003) Mammalian linker-histone subtypes differentially affect gene expression in vivo. Proc Natl Acad Sci U S A 100:5920-5
Eszterhas, Susan K; Bouhassira, Eric E; Martin, David I K et al. (2002) Transcriptional interference by independently regulated genes occurs in any relative arrangement of the genes and is influenced by chromosomal integration position. Mol Cell Biol 22:469-79
Dewan, John C; Feeling-Taylor, Angela; Puius, Yoram A et al. (2002) Structure of mutant human carbonmonoxyhemoglobin C (betaE6K) at 2.0 A resolution. Acta Crystallogr D Biol Crystallogr 58:2038-42

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