Because of the importance of the nervous system in disease manifestations caused by scrapie, we will pursue detailed investigation of neuronal infection with a variety of scrapie agents. We will use a cloned pheochromocytoma cell line, termed PC12, as an in vitro neuronal model to study scrapie. This cell line, in the continued presence of nerve growth factor (NGF). undergoes morphological differentiation and attains many of the biochemical and physiological properties of neurons. In addition, NGF-treated PC12 cells has been shown to support 139A scrapie agent replication. Two major issues will be addressed in this proposal. The first focuses on how the metabolic state of the neuron determines the character of scrapie agent infection. Specific aspects to be investigated include the influence on the course of infection of: the developmental maturity of neurons, the route of viral spread, the effect of trophic factors, and the activity state of the neuron. The objective of these studies will be to determine whether these extraneural influences alter the course of infection. The second issue to be studied is how the physiology and metabolism of neurons is altered during scrapie infection. We will execute detailed investigations of how infection perturbs polypeptide and glycoprotein synthesis, catecholamine and acetylcholine neurotransmitter metabolism, glucose utilization, selected membrane properties, axonal transport, and polyamine metabolism. These studies will provide a better understanding of the scrapie agent-host cell interaction and the potential to investigate the role of similar agents in Senile Dementia of the Alzheimer's Type and other CNS disorders of unknown etiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS025308-04
Application #
3477127
Study Section
Experimental Virology Study Section (EVR)
Project Start
1988-02-01
Project End
1993-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Institute for Basic Research in Dev Disabil
Department
Type
DUNS #
167205090
City
Staten Island
State
NY
Country
United States
Zip Code
10314
Rubenstein, R; Deng, H; Race, R et al. (1994) Scrapie strain infection in vitro induces changes in neuronal cells. Mol Neurobiol 8:129-38
Carp, R I; Callahan, S M; Patrick, B A et al. (1994) Interaction of scrapie agent and cells of the lymphoreticular system. Arch Virol 136:255-68
Rubenstein, R; Deng, H; Race, R E et al. (1992) Demonstration of scrapie strain diversity in infected PC12 cells. J Gen Virol 73 ( Pt 11):3027-31
Rubenstein, R; Merz, P A; Kascsak, R J et al. (1991) Scrapie-infected spleens: analysis of infectivity, scrapie-associated fibrils, and protease-resistant proteins. J Infect Dis 164:29-35
Kascsak, R J; Rubenstein, R; Carp, R I (1991) Evidence for biological and structural diversity among scrapie strains. Curr Top Microbiol Immunol 172:139-52
Kim, Y S; Carp, R I; Callahan, S et al. (1990) Incubation periods and histopathological changes in mice injected stereotaxically in different brain areas with the 87V scrapie strain. Acta Neuropathol 80:388-92
Carp, R I; Kim, Y S; Callahan, S M (1990) Pancreatic lesions and hypoglycemia-hyperinsulinemia in scrapie-injected hamsters. J Infect Dis 161:462-6
Rubenstein, R; Scalici, C L; Papini, M C et al. (1990) Further characterization of scrapie replication in PC12 cells. J Gen Virol 71 ( Pt 4):825-31