This Program Project grant brings together molecular biologists, virologists, immunologists, and experimental biologists to study neurodegenerative, endocrine and renal disorders of aging using transgenic models. The purpose is to understand pathogenesis and to develop therapeutic approaches to treat such disorders. Two interlocking hypotheses are addressed. The first is that expression of amyloid protein, its precursor or mutant proteins, prion or viral proteins in specialized cells of the central nervous system (CNS) using CNS specific promoters for expression in astrocytes or neurons will provide models of neurodegenerative disorders like Alzheimer's Disease. The second hypothesis addresses the issue that environmental agents (viruses) cause diseases in the aging population. It is proposed that acute or persistent infection can cause degenerative progressive diseases of endocrine cells, immunocompetent (lymphocytes) cells, neurons, or cells of the renal glomeruli and tubules. Such diseases; i.e., neurodegenerative, diabetes, glomerulosclerosis, etc., can occur through the ability of a virus to persist in specialized cells (i.e., islets of Langerhans, lymphocytes, neurons, etc.) and turn down such cells differentiation or luxury function (i.e., hormones, cytokines, neurotransmitters, etc.). Such viruses need be non-cytolytic and hence disease occurs by altering a cell's physiologic function in the absence of the cell's destruction. Because virus induced disease can occur in the absence of tissue injury many illnesses not previously thought to be infectious in origin may be so. Studies of this hypothesis utilize investigation of replication of a non-cytolytic virus in differentiated cells in vitro and in vivo as well as transgenic technology to express viral genes in specialized cells using the insulin promotor (beta cells of the islets of Langerhans), GFAP promoter astrocytes) and NSE promoter (neurons). In such instances cell and tissue injury and disease may occur through the expression of the viral gene itself or through the formation and action of antiself (antiviral) cytotoxic T lymphocytes or antibodies following infection or immunization with the homologous or closely related virus (cross-reactive immune response against self) through a process we term molecular mimicry.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG004342-15
Application #
2607637
Study Section
Neuroscience, Behavior and Sociology of Aging Review Committee (NBSA)
Project Start
1983-08-01
Project End
1998-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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