Abstract

We propose experiments in four areas dealing with eq. the formation of sickle hemoglobin (HbS) polymers and their effect on the red blood cell. (1) We shall continue our studies of the structure of HbS fibers which are primarily responsible for the pathological manifestations of sickle cell anemia. (2) Our past studies of the crystallization of fibers has provided important insights regarding the molecular rearrangements which accompany crystallization. We propose to extend these studies by (a) further characterization of the structure of crystallization intermediates (b) computer modeling of the fiber and crystallization intermediates using the crystal as the reference structure and (c) determination of the thermodynamic parameters driving crystallization. (3) Much of the existing knowledge about the polymerization of HbS has been obtained using static systems. We propose experiments in which polymerization of HbS will be studied in red cells subjected to rapidly changing deformation approaching what actually occurs in the vascualr circulation. (4) Finally we propose to investigate the structural changes in the red cell cytoskeleton which result in irreversible sickling.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL022654-11
Application #
3337001
Study Section
Biophysics and Biophysical Chemistry B Study Section (BBCB)
Project Start
1978-07-01
Project End
1991-01-31
Budget Start
1989-04-01
Budget End
1991-01-31
Support Year
11
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Turner, M S; Agarwal, G; Jones, C W et al. (2006) Fiber depolymerization. Biophys J 91:1008-13
Turner, M S; Briehl, R W; Wang, J C et al. (2006) Anisotropy in sickle hemoglobin fibers from variations in bending and twist. J Mol Biol 357:1422-7
Turner, M S; Briehl, R W; Ferrone, F A et al. (2003) Twisted protein aggregates and disease: the stability of sickle hemoglobin fibers. Phys Rev Lett 90:128103
Wang, Jiang Cheng; Turner, Matthew S; Agarwal, Gunjan et al. (2002) Micromechanics of isolated sickle cell hemoglobin fibers: bending moduli and persistence lengths. J Mol Biol 315:601-12
Agarwal, Gunjan; Wang, Jiang Cheng; Kwong, Suzanna et al. (2002) Sickle hemoglobin fibers: mechanisms of depolymerization. J Mol Biol 322:395-412
Ivanova, M; Jasuja, R; Krasnosselskaia, L et al. (2001) Flexibility and nucleation in sickle hemoglobin. J Mol Biol 314:851-61
Wang, Z; Kishchenko, G; Chen, Y et al. (2000) Polymerization of deoxy-sickle cell hemoglobin in high-phosphate buffer. J Struct Biol 131:197-209
Bookchin, R M; Balazs, T; Wang, Z et al. (1999) Polymer structure and solubility of deoxyhemoglobin S in the presence of high concentrations of volume-excluding 70-kDa dextran. Effects of non-s hemoglobins and inhibitors. J Biol Chem 274:6689-97
Fairclough, R H; Twaddle, G M; Gudipati, E et al. (1998) Mapping the mAb 383C epitope to alpha 2(187-199) of the Torpedo acetylcholine receptor on the three-dimensional model. J Mol Biol 282:301-15
Fairclough, R H; Gudipati, E; Lin, M Y et al. (1998) A role for alpha(187-199) in the conversion of agonist binding energy to the opening of the acetylcholine receptor ion channel. Ann N Y Acad Sci 841:87-92

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