BIOCHEMICAL STUDY OF MYELINATION AND DEMYELINATION

Project: Research project

Project Details

Description

The overall objective of this application is to study the biochemical and
immunological basis of demyelination in multiple sclerosis (MS) and
experimental allergic encephalomyelitis (EAE), as well as the biochemical
parameters affecting myelination and remyelination. Our emphasis is placed
on the role of glycosphingolipids (GSLs) in these events. Since GSLs are
localized primarily on the cell surface and are known to undergo cell-
specific, developmentally regulated changes, they serve as excellent
markers for monitoring cellular events occurring during myelination and
demyelination. Their importance in this regard is further underscored by:
(a) the discovery that there are unique glycolipid antigens common to the
nervous system and the endothelial cells, and (b) certain GSLs are powerful
modulators of immune cell growth and differentiation. In the first area of
research, a major goal is to provide additional biochemical data on myelin
breakdown, the associated gliotic reactions, and remyelination. This is
facilitated by the development of several novel and highly sensitive
procedures for analyzing specific cellular GSL components. Immunological
research in MS has been extensive, and there is strong evidence that an
autoimmune mechanism may play an important role in the pathogenesis of this
disease. The autoantigen(s) that are involved in myelin and
oligodendroglial degeneration in MS have not been clearly defined. We
hypothesize that the inflammatory demyelination in MS and EAE may be
triggered by autoreactive T cells specific for CNS myelin proteins and
glycoconjugates, and by humoral response against target antigens
specifically localized in endothelial cells and the CNS. The humoral
response against the endothelium may account for the vascular permeability
change preceding demyelination. This hypothesis will be tested employing
in vitro and in vivo model systems. In the second area of research, we
plan to focus on the synthesis of galactocerebrosides (GC) which are highly
enriched in myelin. Since there are two types of GC, the possibility
exists that they are synthesized by two distinct galactosyltransferases.
We plan to purify these two enzymes and to study their subcellular
localization, and to elucidate the regulation of the enzyme activities
during development by molecular biological techniques. Since
galactosyltransferases are apparently found in oligodendroglial plasma
membrane and myelin, we propose that they may function as membrane adhesion
molecules for the formation of the multilamellar structure of myelin. An
understanding of the synthesis and function of galactocerebrosides should
enhance our knowledge on factors modulating myelination and remyelination.
StatusFinished
Effective start/end date7/1/863/31/95

ASJC

  • Medicine(all)
  • Neuroscience(all)