BIOCHEMICAL ANALYSIS OF MALLORY BODIES IN MOUSE AND MAN

Project Details

Description

Mallory Bodies (MB) are cytoplasmic filamentous inclusions seen primarily
in alcoholic liver disease, although they may also be found in
association with other liver diseases. The primary structural components
of MB are a group of epithelial specific intermediate filament
cytoskeletal proteins termed keratin polypeptides 8 and 18 (K8/18). The
biochemical basis for these abnormally aggregated keratins is presently
unknown. A basic understanding of the nature of keratin modification in
MB should allow designing rational experiments to determine if changes
in keratins are essential for alcohol induced injury and if such changes
can be reversed. Our hypothesis is that Mallory Body formation may result from alterations
in glycosylation and/or phosphorylation of hepatocyte keratins. This
hypothesis is based on finding discrete keratin cytoplasmic dots, that
are morphologically similar to MB, when keratin phosphorylation and
glycosylation increases during cell mitosis. In addition, desmin bodies
which are found in familial myopathy and are derived from the
intermediate filament protein desmin, were found to be
hyperphosphorlated. In carrying out this proposal, we plan to take
advantage of our studies involving the characterization of normal
epithelial keratin glycosylation and phosphorylation. For example, we
recently showed that keratins 8 and 18 are O-linked glycoproteins with
glycosylation sites consisting of single N-acetylglucosamine (GlcNAc)
residues. To test our hypothesis, we plan to study the phosphorylation
and glycosylation of K8/18 in experimentally induced Mallory Bodies in
mice, and in human liver specimen obtained from biopsies or surgical
specimen. We also plan to determine at a detailed molecular level if
other forms of posttranslational modification such as transglutamination
account for MB formation. Finally, we plan to explore the possibility
that primary amino acid structural changes occur in keratins of MB.
StatusFinished
Effective start/end date5/1/934/30/95

Funding

  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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