THE RED CELL CYTOSKELETON AND SICKLE CELL DISEASE

  • 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

Sickle cell anemia is characterized by a multitude of clinical and
cellular abnormalities that arise as a consequence of the presence of the
mutant gene produce hemoglobin S (HbS). Although it is likely that many
of the attendant cellular defects are acquired, the mechanisms by which
they arise are still unknown. The long-term objective of this proposal
is to define the mechanisms responsible for the development of membrane
abnormalities in SS cells. To achieve this objective we will test the
hypothesis that oxidative damage plays a role in the development of
membrane and cytoskeletal protein functional abnormalities in SS cells.
We will focus on the effects of oxidation on key protein components of
the red cell membrane and cytoskeleton, including spectrin, ankyrin and
band 3. Protein oxidative damage will be assessed by binding to
sulfhydryl-specific chemical probes and by direct analysis of protein
amino acids. Additional studies will examine protein function to
determine if function has been altered by oxidative modifications.
Interactions between spectrin and calmodulin will be studied to determine
if abnormal interactions between these proteins plays a role in the
generation of irreversibly-sickled cells. Functional studies will
determine if enzymes involved in maintaining protein sulfhydryl
homeostasis, such as thioltransferase, are damaged in SS cells. The role
of the sickling event per se in the development of protein oxidative
lesions will be examined in oxygenated-deoxygenated cycling studies. The
antioxidant capacity of defined SS cell populations will be measured to
determine if oxidative damage results from a decreased capacity of some
SS cells to repair oxidative lesions. The role of protein oxidation in
the development of morphologic abnormalities will be studied by
fluorescent and electron microscopy using sulfhydryl-specific chemical
probes. The role of protein oxidation in the development of
abnormalities in cell volume regulation will be studied using defined
cells with high of low K:C1 cotransport activity. The role of HbS
binding to the membrane and iron decompartmentalization in the
development of cell morphologic and protein functional abnormalities will
be tested in transgenic HbS mice with defined amounts of HbS. Together,
these studies may help to elucidate the mechanisms responsible for the
development of membrane abnormalities in SS cells and better our
understanding of the pathophysiology of this disease and of other
hemoglobinopathies characterized by unstable hemoglobins.
StatusFinished
Effective start/end date1/1/019/30/03

Funding

  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute

ASJC

  • Anesthesiology and Pain Medicine
  • Genetics
  • Molecular Biology
  • Hematology
  • Radiology Nuclear Medicine and imaging
  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Public Health, Environmental and Occupational Health
  • Nephrology
  • Pathophysiology
  • Social Sciences(all)
  • Polymers and Plastics
  • Medicine(all)
  • Ophthalmology
  • Pathology and Forensic Medicine

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