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.
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