KINETICS &ASSEMBLY OF HEMOGLOBIN S FIBERS &GELS

  • Briehl, Robin W. (PI)

Project: Research project

Project Details

Description

The central pathophysiologic event in sickle cell disease is the formation
of an intraerythrocytic gel of deoxyhemoglobin S, resulting in
intracellular and vascular rheological events which produce obstruction.
The overall aim of this work is to elucidate the kinetics and mechanisms of
assembly of hemoglobin S gels with the health related purposes of
understanding the molecular mechanisms of pathogenesis in, and developing a
specific therapy, not now existent, for sickle cell disease. The
fundamental rationale for this approach is based on accumulating evidence
that pathogenesis and its marked variability depend on the physical
chemistry, and particularly the kinetics of gelation and its highly mutable
nature. This mutability results from the existence of metastable states
and highly cooperative phenomena. Gle assembly occurs in three
experimentally defined stages: (a) nucleation (during which no significant
rheological changes occur), (b) growth of long, rod-like fibers from nuclei
and (c) alignment of these fibers to form liquid crystalline regions
(tactoids), associated with separation into conugate anisotropic and
isotropic phases. Most of the work planned will address pre-gelation
aggregation, either of the kinetic kind, occurring during the first stage,
or of the equilibrium kind, occurring at concentrations of hemoglobin S
which are insufficient to induce gelation. Low angle elastic light
scattering and quasi-elastic light scattering will be used for most
studies, supplemented by electgron and polarizing microscopy and
rheological measurements. The specific aims are to characterize the
aggregates observed in respect to molecular weight, shape (as measured by
radius of gyration, excluided volume non-ideality, and diffusion
coefficient), sequence of development and alignment.
StatusFinished
Effective start/end date4/1/823/31/88

ASJC

  • Medicine(all)