PATHOGENESIS OF HEREDITARY TRANSTHYRETIN AMYLOIDOSIS

Project: Research project

Description

The overall objective of this proposal is to understand the pathophysiology
of the autosomal dominant transthyretin (prealbumin) amyloidoses. These
diseases, which affect a number of kindreds worldwide and with large
families in the United States are manifest as peripheral neuropathy,
nephropathy and cardiomyopathy. They are late-onset diseases but are
associated with high degrees of morbidity and mortality. Several of these
syndromes have been found to be associated with mutations in the gene for
transthyretin (prealbumin) which result in single amino acid substitutions.
How these mutations lead to amyloid fibril formation and disease expression
is not known. These studies will investigate the pathophysiology of the process leading
to clinical disease and will test the hypothesis that the single amino acid
substitutions associated with amyloidosis cause 1) changes in metabolism of
the variant molecule compared to normal and 2) identifiable changes in the
secondary and tertiary structures of the variant protein. It is proposed
that this change in structure and its metabolic consequences lead directly
to amyloid fibril formation and then the clinical disease. These aims will
be accomplished by synthesizing recombinant variant transthyretin proteins
in order to have variants separated from normal transthyretin. This will
allow evaluation of the metabolism of the amyloid precursor proteins. It
will also allow study of the tertiary structure of the variant
transthyretin molecules. Crystallographic data already obtained on one
mutant transthyretin (Met-30) which was obtained from homozygous
individuals' plasma has shown that this method is feasible and practical.
These data will be compared to normal transthyretin and a model formulated
to explain the factors involved in polymerization to form amyloid fibrils. Accomplishment of these specific aims will allow identification of crucial
factors in the pathophysiology of amyloid fibril formation and may lead to
methods to prevent amyloid formation and therefore disease expression.
StatusFinished
Effective start/end date8/1/9011/30/04

Funding

  • National Institutes of Health: $187,467.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $119,652.00
  • National Institutes of Health: $260,750.00
  • National Institutes of Health: $260,969.00
  • National Institutes of Health: $164,508.00
  • National Institutes of Health: $254,380.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $243,600.00

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Familial Amyloidosis
Prealbumin
Amyloid
Cardiomyopathies
Amino Acid Substitution
Amyloidosis
Amyloidosis, Hereditary, Transthyretin-Related
Mutation
Peripheral Nervous System Diseases
Amyloid beta-Protein Precursor
Tertiary Protein Structure
Morbidity
Polymerization

ASJC

  • Medicine(all)