STRUCTURAL ASPECTS OF ABPP FUNCTION AND PATHOLOGY

Project Details

Description

The long-term objective of the laboratory is a detailed characterization of
the structure and the function of the Alzheimer's amyloid beta protein
precursor (ABPP). Besides being implicated in Alzheimer's disease, this
protein has recently been found in platelets, and a mutant version of the
beta peptide itself has been linked to a hereditary cerebral hemorrhage,
HCHWA-D. A description of the functional (or dysfunctional) behavior of
ABPP in normal and pathological states might suggest new therapeutic
approaches to the treatment of neurodegenerative diseases such as
Aizheimers as well as cardiovascular disorders such as stroke. With these objectives in mind, the thrust of our proposed research is
two-fold: a) to derive further high-resolution structural information about
ABPP which might yield insights into function; and b) use the structural
information that we already have to try to identify proteins in the brain
and in the blood that specifically interact with ABPP or its subfragments.
Our specific aims for the term of the grant are: 1. To begin a comprehensive study of the structure and function of ABPP by
conducting a high resolution "alanine scan" of the N-terminal domain. 2. To produce large quantities of purified, recombinant ABPP N-terminal
domain for structural studies by X-ray crystallography and multidimensional
NMR. 3. To study the possible role of beta amyloid fibrils as stimulators of
human tissue plasminogen activator. 4. To isolate molecular clones of cognate proteases or esterases that bind
to the ABPP Kunitz domain. This work, if successful, should start to bring into focus the network of
proteins in the body, both in the brain and in the blood, that interact
with ABPP. This information will help elucidate the role ABPP plays both
in healthy and in diseased tissue.
StatusFinished
Effective start/end date9/30/926/30/00

Funding

  • National Institutes of Health
  • National Institutes of Health: $316,564.00
  • National Institutes of Health
  • National Institutes of Health: $229,965.00
  • National Institutes of Health
  • National Institutes of Health: $302,755.00

ASJC

  • Medicine(all)

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