CYTOSKLETON PROTEINS &RED CELL VOLUME REGULATION--VOLUME SENSITIVE ION CHANNELS

  • Bouhassira, Eric E. (PI)
  • Lutty, Gerard Anthony (PI)
  • Kaul, D. (PI)
  • Acharya, Seetharama A. (PI)
  • Croizat, Helena (PI)
  • Fabry, Mary (PI)
  • Schwartz, Robert (PI)
  • Benjamin, Lennette (PI)
  • Nagel, Ronald (PI)
  • Kaul, D. (PI)
  • Croizat, Helena (PI)
  • Fabry, Mary (PI)
  • Schwartz, Robert (PI)
  • Benjamin, Lennette (PI)
  • Nagel, Ronald (PI)

Project: Research project

Project Details

Description

(Adapted from Applicant's Abstract) Cell volume regulation is a necessary
feature of human red cell (RBC) differentiation and in disease states
with reticulocytosis and young cells. In sickle cell (SS), SC and CC
disease, abnormal volume regulation leads to cell dehydration and
pleiotropic pathological events. Unfortunately, RBC volume control is
poorly understood, in particular, due to the lack of molecular
identification of proteins responsible for volume regulation, and little
understanding of the mechanisms by which these proteins are regulated. The
major goals of this proposal are to molecularly define RBC volume-
sensitive ion transporter/channel proteins and to understand the
structural and regulatory responses these proteins undergo to restore
normal volume. The investigators are particularly interested in defining
the role of the cytoskeleton in transducing volume signals to the ion
transporters/channel and whether direct interactions between cytoskeleton
proteins and these proteins are involved int heir regulation. These goals
will be addressed by the following specific aims: (1) Molecularly identify
proteins responsible for RBC volume-sensitive ion transport: pICln, K:C1
co-transporter (K:C1-CT), and Na-K-C1 co-transporter (Na-K-2C1-CT); and
crete cell and animal models expressing these ion transporters/channels.
(2) Define the role of band 3 oligomeric state in volume-sensitive signal
transduction and regulation of ion transporter/channel activity, and test
the hypothesis that protein phosphorylation-dephosphorylation is a common
mechanism for ion transport/channel regulation. If so, identify the
phosphorylation sites. (3) Test the hypothesis that hemoglobin (Hb)
binding to ion transport proteins/channels affects and cytoskeleton
proteins. Define mechanisms by which cytoskeleton regulation of cell
volume is affected. (5) Formulate models from this information, and test
the models in erythroid cell lines where specific cytoskeleton
deficiencies are induced using ribozyme and antisense technology. The
studies should greatly increase the understanding the RBC volume
regulation. This information will allow for sensible strategies aimed at
preventing RBC dehydration, which would have a potentially significant
impact on future drug or gene-based therapies for SS, SC, and CC diseases.
StatusFinished
Effective start/end date10/1/973/31/99

Funding

  • National Heart, Lung, and Blood Institute

ASJC

  • Drug Discovery
  • Medical Laboratory Technology
  • Anesthesiology and Pain Medicine
  • Genetics
  • Cellular and Molecular Neuroscience
  • Molecular Medicine
  • Molecular Biology
  • Developmental Neuroscience
  • Hematology
  • Biophysics
  • Structural Biology
  • Physiology
  • Biochemistry
  • Radiology Nuclear Medicine and imaging
  • Pulmonary and Respiratory Medicine
  • Behavioral Neuroscience
  • Cell Biology
  • Pharmacology
  • Histology
  • Hepatology
  • Developmental Biology
  • Immunology

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