Antagonizing NOS Activity to Induce Neurogenesis in the*

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DESCRIPTION (provided by applicant) Nitric oxide (NO) acts as an essential antiproliferative signal during tissue differentiation and development. We have recently found that we can inhibit NO production and cause an increase in the number of dividing cells in the adult rodent brain by introducing NO synthase (NOS) inhibitors into brain ventricles. This increase was evident in several areas of the adult brain; significantly, we showed this effect in the areas which have very low levels of neurogenesis, including the cortex and striatum. In this proposal we plan to examine whether introducing NOS inhibitors into brains previously lesioned by neurotoxic agents can induce proliferation of nigrostriatal neurons. We also propose to use a line of transgenic mice, where neural stem cells are marked by GFP expression, to follow the fate of transplanted cells in animal models of Parkinson's disease, and to augment the proliferation of these cells by blocking NOS activity. We further propose to generate a double-transgenic mouse line where neural stem cells and differentiated dopaminergic neurons will be marked by the expression of two different fluorescent proteins. This proposal directly relates to the purpose of this RFA as stated in the guidelines: it proposes a strategy for reversing the pathogenesis of Parkinson's disease and it proposes developing an animal model for the studies of the disease.