Immunological Inducible Nitric Oxide Synthase (iNOS enzyme and NOS2 gene) found in microglia and macrophages, releases NITRIC OXIDE which is reported to be toxic in some, and protective in other, experimental paradigms of human disease. Aberrant microglial activation in Multiple Sclerosis (MS), stroke, severe head trauma and Alzheimer's Disease (AD), can directly contribute to neurotoxicity and tissue destruction through inflammation which includes release of reactive oxygen species, proteases, cytokines and excitatory neurotransmitters. In peripheral tissues, macrophage mediated nitric oxide release appears to contribute to rheumatoid arthritis and inflammatory bowel disease. The induction of iNOS activity to release nitric oxide is highly regulated and is also regulated in a species specific manner. In Phase I of the SBIR, we propose to make an animal model that releases the nitric oxide oxyradical in a fashion similar to that found in humans, that is, a """"""""Humanized-Nitric Oxide Synthase, type 2"""""""" transgenic mouse (Humanized -NOS2 Tg mouse). This transgenic will only express human-NOS2 enzyme and in Phase II, its regulation of nitric oxide release will be tested for its similarity to the human-specific pattern. Such a mouse model will have broad utility to more accurately predict the role played by oxyradicals in the development of human disease which will be extensively tested in Phase II of this application.
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