SPHINGOGLYCOLIPIDS IN NORMAL AND PATHOLOGICAL BRAINS

Project: Research project

Project Details

Description

The major objective of this project is to study the chemistry and
metabolism of gangliosides during nervous system development. Earlier
studies have demonstrated that the ganglioside composition of mammalian
brains changes dramatically during development. Since membrane
gangliosides are known to play important roles in diverse cellular
functions such as cell-cell interaction and adhesion, growth inhibition,
differentiation and proliferation, the strict regulation of their
metabolism is required for normal cellular function. As a first step we
will define and determine the structures and distributional pattern of
these stage-specific glycosphingolipids that are involved in cellular
growth and differentiation, particularly during early nervous system
development. We will continue to seek new biosynthetic pathways for their
synthesis. At present our knowledge on the molecular basis of ganglioside
metabolism is limited. To delineate the metabolic basis of the
developmental changes in cell surface gangliosides, we will focus on
several glycosyltransferases that are situated at the key regulatory points
for their synthesis. We will first achieve the isolation and purification
of these enzymes in order to study their biochemical and molecular
properties. We will further apply immunocytochemical techniques to define
their cellular and subcellular localization, and molecular biological
techniques to examine how the expression of these enzymes, as a family of
closely related gene products, is regulated at various stages of brain
development. Since the striking development changes in ganglioside
composition of brain cells depend ultimately on an intricate balance in
their synthesis and degradation, we will also focus on a key enzyme,
neuraminidase, in this process. As neuraminidase is also known to regulate
cellular growth and differentiation, we will examine how modulation of
ganglioside catabolism by this enzyme may be involved in the regulation of
ganglioside expression in developing nervous system. The long-term goal of
these studies is to better understand the expression and regulation of cell
surface gangliosides in the developing nervous system. An understanding of
the molecular mechanisms underlying the differentiation of nerve cells
should greatly enrich our knowledge in the function of gangliosides in
normal brain development as well as in neurological disorders that result
in mental retardation.
StatusFinished
Effective start/end date6/1/788/31/12

ASJC

  • Medicine(all)
  • Neuroscience(all)