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.
Showing the most recent 10 out of 181 publications
