Abstract

Genetic control of sickle red cell dehydration in mice, dehydration accelerates polymerization of deoxy-hemoglobin S, leading to increased cell sickling. The major role in cell dehydration, the K-CI co-transport system and the Ca2+-activated K channel. The activation in sickle cell disease is crucial not only to understand sickle cell dehydration but also to this proposal are 1) to extend the functional characterization of the expressed mouse K-CI cotransporter blood cells and 2) the study of in vivo down-modulation of the K-CI co-transport pathway in transgenic mouse models of sickle cell disease. These objectives will be reached through the accomplishment of the following Specific Aims.
Specific Aim 1. Further functional characterization of the mouse K-CI cotransporter (KCC1) and its mutants expressed in Xenopus oocytes.
Specific Aim 2. Generation of normal and sickle mice with reduced or absent erythroid KCC1.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
2F32HL009853-03
Application #
6056141
Study Section
Special Emphasis Panel (ZRG1-HEM-2 (01))
Project Start
1999-10-01
Project End
Budget Start
1999-10-01
Budget End
2000-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$46,300
Indirect Cost

  Institution

Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Roussa, Eleni; Shmukler, Boris E; Wilhelm, Sabine et al. (2002) Immunolocalization of potassium-chloride cotransporter polypeptides in rat exocrine glands. Histochem Cell Biol 117:335-44
Shmukler, B E; Bond, C T; Wilhelm, S et al. (2001) Structure and complex transcription pattern of the mouse SK1 K(Ca) channel gene, KCNN1. Biochim Biophys Acta 1518:36-46
Casula, S; Shmukler, B E; Wilhelm, S et al. (2001) A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity. J Biol Chem 276:41870-8
Papageorgiou, P; Shmukler, B E; Stuart-Tilley, A K et al. (2001) AE anion exchangers in atrial tumor cells. Am J Physiol Heart Circ Physiol 280:H937-45
Shmukler, B E; Brugnara, C; Alper, S L (2000) Structure and genetic polymorphism of the mouse KCC1 gene. Biochim Biophys Acta 1492:353-61
Zolotarev, A S; Shmukler, B E; Alper, S L (1999) AE2 anion exchanger polypeptide is a homooligomer in pig gastric membranes: a chemical cross-linking study. Biochemistry 38:8521-31
Alper, S L; Rossmann, H; Wilhelm, S et al. (1999) Expression of AE2 anion exchanger in mouse intestine. Am J Physiol 277:G321-32