Parkinson's disease (PD) derives from the confluence of advancing age, inherited susceptibility, and environmental exposures. While the mechanisms involved are not yet clear, inherited abnormalities in alpha- synuclein (SNCA) and exposure to selected toxicants can mimic some of the facets of PD in rodent models. We propose that the point of convergence for these processes is innate immune activation, especially in the substantia nigra, which may have both deleterious and beneficial effects on neuronal survival. The prostaglandin E2 pathway, a major component of activated innate immunity, is effected through a family of four G-protein coupled receptors called EP1 through EP4. We will test the hypothesis that EP receptor subtypes are fundamentally important in determining the balance of neurotrophic vs. neurotoxic effects of innate immune activation. We will test our hypothesis through Specific Aims that use a genetically altered mouse models and potentially relevant toxicant models: MPTP and cytokine cocktails that mimic the central nervous system effects of peripheral endotoxin exposure. This application is responsive to several points in the NIH Blueprint: it is a direct response to the therapeutic imperative for PD, it is highly translational, and it draws on existing NIH-funded resources. When successfully completed, our proposed work will have advanced and refined our knowledge about potentially important new therapeutic targets that complement other ongoing efforts to protect dopaminergic neurons from innate immune activation and to reduce pathologic forms of SNCA in brain.
We and others already have shown in rodent models that activation of innate immune response with increased production of prostaglandin (PG) E2 damages the same dopaminergic neurons that degenerate in Parkinson's disease (PD). In addition, increased generation of PGE2 in diseased regions of brain is a feature of patients with PD. Here we propose to focus on the PGE2 receptors, called EP1 through EP4, with the goal of developing new therapeutic targets for PD. We will test our hypothesis using genetically altered mouse models combined with potentially relevant environmental toxicant models: MPTP and cytokine cocktails that mimic the central nervous system effects of peripheral endotoxin exposure. When successfully completed, our proposed work will have advanced and refined our knowledge about potentially important new therapeutic targets that complement other ongoing efforts to protect dopaminergic neurons from innate immune activation in patients with PD.
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