SICKLE HEMOGLOBIN: PHYSICAL CHEMISTRY &PATHOGENESIS

  • Briehl, Robin W., (PI)

Project: Research project

Description

The long term objectives of this project are to characterize the equilibria
and kinetics of the polymerization and gelation of sickle cell hemoglobin
and, through understanding of this physical chemistry (which is responsible
for pathogenesis), to develop a specific therapy for sickle cell disease. Specific aims concern kinetics, properties of the formed gel, and
elucidation of relations between physical chemistry and clinical events.
Kinetics will be examined principally by rheological methods, in some
protocols in conjunction with optical methods, particularly light
scattering. The course of increase of viscosity (and other properties)
will be followed to ascertain the basic shape of the progress curve and in
order to deduce mechanisms of gel assembly and values of the kinetic
constants for the various reactions. Characterization will include
ascertaining the distribution of hemoglobin S fiber lengths as the
polymerization progresses. In addition, the effects of shearing on the
kinetics will also be ascertained, as will the effects of solution
conditions and various parameters which might have in vivo relevance. Since the gel is responsible for decreased red cell deformability and
pathogenesis, its mechanical properties are important. Therefore, the
solid-like, viscous and thixotropic properties of viscoplastic gels will be
measured, as will equilibrium pressure-volume properties. Thermodynamic
properties to be studied include phase relations in this two phase system,
and the effects of various physiological moieties (2,3 diphosphoglycerate
and protons) on gel properties. Studies will also be directed to the
structure of hemoglobin S fibers and to liquid crystals, a basic element in
the gel. These studies have many potential clinical relations. For example, shear
occurs within red cells in the circulation, altering the vents of gelation
markedly. Other factors, such as nuclei for gelation which are never
melted upon oxygenation, may do the same. Thermodynamic properties such as
the effects of 2,3 diphosphoglycerate and protons also may have significant
clinical effects. In general, the kinetics of gelation are highly mutable
with minor changes in conditions and the equilibria may be also somewhat
mutable in cooperative fashion. If this lability is understood it may
permit small physiological modifications which greatly ameliorate the
course of sickle cell disease.
StatusFinished
Effective start/end date6/1/767/31/94

Keywords

  • Medicine(all)