The
bioactive peptides are the largest and least understood class
of intercellular messengers, carrying out a diverse set of functions
in a wide variety of systems. Understanding bioactive peptides
and their receptors, in the nervous system and elsewhere, is the
general research goal in our group.
One
system of interest is the tachykinin (substance P) family of peptides
and receptors, which are involved in transmission of primary afferents
and thus in pain and neurogenic inflammation. As the primary structures
of both the ligands and their receptors are known, an excellent
model system for peptide-protein interactions in signalling is
available. Recently we have identified through photoaffinity labelling
which regions of the peptide substance P interact with which regions
of its G-protein-coupled receptor, a protein whose expression
is upregulated a thousand-fold in some inflammatory diseases.
Radioactive, fluorescent, and antibody probes of these receptors
allow studies of desensitization and internalization in vivo and
in vitro.
Another
system under investigation is the process of amyloid formation
in Alzheimer's disease (AD) and other amyloidoses. The characteristic
lesion of AD is brain senile plaques formed mainly of the human
amyloid peptide Ab, a *40-mer which occurs naturally in normal
as well as AD brain. By reconstituting plaque growth (deposition
of Ab at physiological concentrations onto authentic plaques)
in vitro, we can characterize the process and identify conditions
and components which enhance or inhibit its kinetics. Structure/activity
studies have identified amino acids critical for amyloid deposition
and active peptide analogues suitable for high resolution structure
determination by nuclear magnetic resonance spectroscopy. The
latter studies have further identified conformational elements
essential to plaque deposition.
Another
interest is the characterization of novel bioactive peptides from
natural sources. A particularly rich source is the skin venom
of certain neotropical frogs. The peptides found here include
antibiotics and toxins as well as close analogs of discovered
and yet undiscovered mammalian neuropeptides.
Publications
