This proposal is for continuing a highly successful Program Project grant that links the fields of virology, molecular genetics and immunology to approach the problem of degenerative of aging with a focus on neurodegenerative and pancreatic. Through the use of targeted transgenic animal models, complemented with models of persistent viral infection, we seek a greater understanding of the pathogenesis of neuronal diseases caused by PrP (prions), beta-amyloid precursor proteins or persistent expression of viral genes, and the effects of persistent viral gene expression and antiviral (self) immune responses on beta cells of the islets of Langerhans. Such studies will allow the development of novel forms of therapeutic intervention. Two interlocking hypotheses are addressed. The first is that expression of amyloid protein, its precursor or mutant proteins, prions or viral proteins in specialized cells of the central nervous system (CNS) using CNS-specific promoters for expression in astrocytes or neurons provide models of neurodegenerative disorders like Alzheimer's disease. It is also proposed that persistent infections can cause progressive degenerative disease. In this instance disease occurs owing to the ability of a virus to persist in specialized cells and turn down the ability of those cells to make differentiation or luxury function products such as GAP-43, neurotransmitters, hormones, cytokines, etc. The second hypothesis is that initiation of the immune-response or alterations in immune responses to PrP, beta-amyloid, viral or other related proteins can contribute to these degenerative disorders. Protocols are designed to test the various possibilities to address both pathogenic mechanisms and therapeutic interventions. We believe these targeted models that we have developed closely resemble aspects of corresponding human diseases, allowing us the unique opportunity to attempt novel, discrete, and localized means of anti-viral and other therapies, and immune intervention that will have relevance to the clinical disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG004342-19
Application #
6475582
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Monjan, Andrew A
Project Start
1983-08-01
Project End
2003-11-30
Budget Start
2001-12-15
Budget End
2002-11-30
Support Year
19
Fiscal Year
2002
Total Cost
$1,255,043
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Oldstone, Michael B A (2014) Molecular mimicry: its evolution from concept to mechanism as a cause of autoimmune diseases. Monoclon Antib Immunodiagn Immunother 33:158-65
Priola, Suzette A; Ward, Anne E; McCall, Sherman A et al. (2013) Lack of prion infectivity in fixed heart tissue from patients with Creutzfeldt-Jakob disease or amyloid heart disease. J Virol 87:9501-10
Siggs, Owen M; Cruite, Justin T; Du, Xin et al. (2012) Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease. Proc Natl Acad Sci U S A 109:13733-8
Sun, Binggui; Halabisky, Brian; Zhou, Yungui et al. (2009) Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer's Disease. Cell Stem Cell 5:624-33
Trifilo, Matthew J; Sanchez-Alavez, Manuel; Solforosi, Laura et al. (2008) Scrapie-induced defects in learning and memory of transgenic mice expressing anchorless prion protein are associated with alterations in the gamma aminobutyric acid-ergic pathway. J Virol 82:9890-9
Biasini, Emiliano; Seegulam, M Esa; Patti, Brianna N et al. (2008) Non-infectious aggregates of the prion protein react with several PrPSc-directed antibodies. J Neurochem 105:2190-204
Balch, William E; Morimoto, Richard I; Dillin, Andrew et al. (2008) Adapting proteostasis for disease intervention. Science 319:916-9
Trifilo, Matthew J; Ying, Ge; Teng, Chao et al. (2007) Chronic wasting disease of deer and elk in transgenic mice: oral transmission and pathobiology. Virology 365:136-43
Trifilo, Matthew J; Yajima, Toshitaka; Gu, Yusu et al. (2006) Prion-induced amyloid heart disease with high blood infectivity in transgenic mice. Science 313:94-7
Leclerc, E; Serban, H; Prusiner, S B et al. (2006) Copper induces conformational changes in the N-terminal part of cell-surface PrPC. Arch Virol 151:2103-9

Showing the most recent 10 out of 181 publications