Protein deposition is responsible for a wide range of neurological and systemic disorders, including transmissible spongiform encephalopathies (TSEs) and Alzheimer's disease (AD). The goal of this research is to elucidate the kinetics and mechanism responsible for the accumulation of prion proteins (PrPs), which are implicated in TSEs, and for amyloid (i.e. insoluble fibrillar protein) formation by the A Beta peptide, which is implicated in AD. An understanding of the kinetics and mechanism of aggregation will allow rational therapeutic strategies to be developed for treatment of the disease. Singly spin labeled peptides, derived from PrP and A Beta, will be synthesized and studied by both electron spin resonance (ESR) spectroscopy and electron microscopy (EM) to determine the kinetics of aggregation and amyloid formation. A rapid mixing system will be constructed for the ESR spectrometer so that amyloid formation can be quickly induced, via a solution mixing process, and the kinetics monitored from the onset of favorable aggregation conditions. A series of doubly spin labeled peptide analogs will be made and studied by ESR to determine the nature of the conformational change required for aggregation. Experiments on the double labeled material will also provide information about the conformation of the peptide when it exists as a free monomer in solution and when it is in an aggregated state. Together, these experiments will assist in providing a complete picture of the sequence of events leading to aggregation and amyloid formation by PrP and A Beta.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AG005830-01
Application #
2773991
Study Section
Special Emphasis Panel (ZRG3-BIO (01))
Project Start
1999-03-29
Project End
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064