investigator s abstract: Sickle cell disease arises from the polymerization of sickle hemoglobin by a double nucleation mechanism involving homogenous nucleation in solution and heterogeneous nucleation into sickle hemoglobin polymer surfaces. While the conceptual features of that mechanism have been validated, its predictive power is limited by the lack of a structural foundation and a flawed description of heterogeneous nucleation in the presence of non-polymerizing molecules. The experimental core of this proposal is to assemble a data base of solubility (csat), homogeneous and heterogeneous nucleation rates and elongation rates, for sickle hemoglobin assembly as a function of solution conditions (T, pH, non-ideality) and for various amino acid substitutions. Sickle hemoglobin mutants with additional amino mutations will primarily be provided by Dr. James Manning of Rockefeller University, and the hemoglobin of the SAD mouse will be provided by Dr. Frank Costantini of Columbia University. These data will be used to test and refine a new structural model for heterogeneous nucleation which are proposed herein. The data will also allow the description of heterogeneous nucleation to be extended to describe gelation in the presence of oxygen, fetal Hb, or other non-polymerizing species. This work will ultimately provide an energetic map of the interactions which create the rigid, vasoocclusive gel.
| Yosmanovich, Donna; Rotter, Maria; Aprelev, Alexey et al. (2016) Calibrating Sickle Cell Disease. J Mol Biol 428:1506-14 |
| Tokarev, Alexander; Aprelev, Alexey; Zakharov, Mikhail N et al. (2012) Multifunctional magnetic rotator for micro and nanorheological studies. Rev Sci Instrum 83:065110 |
| Weng, Weijun; Ferrone, Frank A (2011) Metastable gels: A novel application of Ogston theory to sickle hemoglobin polymers. Biophys Chem 154:99-101 |
| Rotter, Maria; Yosmanovich, Donna; Briehl, Robin W et al. (2011) Nucleation of sickle hemoglobin mixed with hemoglobin A: experimental and theoretical studies of hybrid-forming mixtures. Biophys J 101:2790-7 |
| Rotter, Maria A; Chu, Haiyan; Low, Philip S et al. (2010) Band 3 catalyzes sickle hemoglobin polymerization. Biophys Chem 146:55-9 |
| Zakharov, Mikhail N; Aprelev, Alexey; Turner, Matthew S et al. (2010) The microrheology of sickle hemoglobin gels. Biophys J 99:1149-56 |
| Weng, Weijun; Aprelev, Alexey; Briehl, Robin W et al. (2008) Universal metastability of sickle hemoglobin polymerization. J Mol Biol 377:1228-35 |
| Aprelev, Alexey; Weng, Weijun; Zakharov, Mikhail et al. (2007) Metastable polymerization of sickle hemoglobin in droplets. J Mol Biol 369:1170-4 |
| 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 |
| Rotter, Maria A; Aprelev, Alexey; Dragos, Dana et al. (2004) Aspartame has no effect on the polymerization of sickle hemoglobin. Clin Pharmacol Ther 75:248-9 |
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