Structure Interaction and Mechanism in Sickle Hemoglobin

  • Briehl, Robin W. (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant):
The overall aim of this highly cooperative project is to characterize basic pathogenic processes
in sickle cell crises and disease in order to develop treatments and prevention. We focus on a
primary event in crises, polymerization of deoxygenated hemoglobin S (HbS) into rod-like fibers
which form a rigid gel that induces microvascular obstruction. We address four themes, each
with a major pathogenic role. 1) The rigidity of HbS fibers. Gel rigidity depends on fiber rigidity
and the number and character of non-covalent interfiber cross-links. We will extend our recent
characterization of fibers to study of the full gel and measurement of interfiber cross-linking
forces. Also, vibrational entropy has been shown to be important governing the solubility of
HbS. Since this entropy correlates with flexibility, we will study the effect of mutations with known effects on solubility on vibrational entropy and fiber rigidity. 2) Kinetics, equilibria and structure. The nucleation dependent, cooperative, kinetics of polymerization kinetics are central in pathogenesis. We seek to ascertain if the first nucleations might occur on red cell membranes
as well as homogeneously in bulk solution. We also aim to identify the molecular site of
subsequent nucleations, known to occur on existing fibers and responsible for the exponential
nature of polymerization progress. 3) Depolymerization. Having recently characterized aspects
of the mechanisms of depolymerization, we postulate that it too is critical in pathogenesis. We
seek a model for rates and mechanisms for application to depolymerization within the
pulmonary capillaries and during resolution of crises. 4) The red cell. The deleterious effects of
solid-like rheology and rapid kinetics operate through effects on the red cell. We will examine
the role of the membrane in polymerization and the effects of polymerization on it. Our
expertise includes structural methods (EM, microscopy of fibers and gels) as well as physical
chemical methods, theoretical analyses and red cell studies.
StatusFinished
Effective start/end date8/6/9712/31/08

Funding

  • National Heart, Lung, and Blood Institute: $1,934,745.00
  • National Heart, Lung, and Blood Institute: $1,943,663.00
  • National Heart, Lung, and Blood Institute: $1,878,683.00

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