Abstract

Clinicians have long been aware that not all patients with sickle cell anemia follow the same clinical course despite the fact that they all have the identical genetic abnormality. Some are more anemic than others, the frequency of vaso-occlusive events vary, and life expectancy differs. There are several reasons why the red blood cell (RBC) membrane is likely to be one of the most important modulators of clinical severity. First, it is the structure most intimately associated with HbS, and is therefore vulnerable to damage by its prodding and noxious byproducts. Second, it influences the concentration of HbS in the cell. And third, the membrane is the face of the cell that is recognized by proteins and cells in the blood, along the vasculature, and in the reticuloendothelium. In this proposal we focus on two main areas: (1) studying the abnormal membrane protein interactions of sickle cells - those involving ankyrin and protein 3, and (2) cloning and characterizing a membrane protein(s) that influence(s) the concentration of hemoglobin in the cell - the water channel.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Comprehensive Center (P60)
Project #
5P60HL015157-26
Application #
6241520
Study Section
Project Start
1997-04-01
Project End
1998-03-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
26
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118

  Publications

Steinberg, Martin H; Sebastiani, Paola (2012) Genetic modifiers of sickle cell disease. Am J Hematol 87:795-803
Loscalzo, Joseph (2012) Irreproducible experimental results: causes, (mis)interpretations, and consequences. Circulation 125:1211-4
Vandorpe, David H; Xu, Chang; Shmukler, Boris E et al. (2010) Hypoxia activates a Ca2+-permeable cation conductance sensitive to carbon monoxide and to GsMTx-4 in human and mouse sickle erythrocytes. PLoS One 5:e8732
Jahangir, Eiman; Vita, Joseph A; Handy, Diane et al. (2009) The effect of L-arginine and creatine on vascular function and homocysteine metabolism. Vasc Med 14:239-48
Casula, Sabina; Zolotarev, Alexander S; Stuart-Tilley, Alan K et al. (2009) Chemical crosslinking studies with the mouse Kcc1 K-Cl cotransporter. Blood Cells Mol Dis 42:233-40
Steinberg, Martin H; Voskaridou, Ersi; Kutlar, Abdullah et al. (2003) Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 72:121-6
Ware, Russell E; Eggleston, Barry; Redding-Lallinger, Rupa et al. (2002) Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy. Blood 99:10-4
Mirchev, R; Golan, D E (2001) Single-particle tracking and laser optical tweezers studies of the dynamics of individual protein molecules in membranes of intact human and mouse red cells. Blood Cells Mol Dis 27:143-7
Jiang, L; Jha, V; Dhanabal, M et al. (2001) Intracellular Ca(2+) signaling in endothelial cells by the angiogenesis inhibitors endostatin and angiostatin. Am J Physiol Cell Physiol 280:C1140-50
Shmukler, B E; Brugnara, C; Alper, S L (2000) Structure and genetic polymorphism of the mouse KCC1 gene. Biochim Biophys Acta 1492:353-61

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