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Human in vitro model of neuro-inflammation


Parkinson's Disease (PD) is the most common neurodegenerative movement disorder. Historically, PD has been considered a strictly neuronal disease; however, clinical observations and evidence from animal models suggest inflammation may contribute to disease progression. It remains controversial whether glial activation, and the resulting inflammatory cascade, is a result or a cause of neuronal death. Towards resolving this distinction, I established cultures of human embryonic stem cell derived dopaminergic neurons, and primary human astrocytes and microglia. These neural cells are used to investigate the glial inflammatory response to extracellular insults, and the neuronal response to pro- inflammatory mediators. I established that these cells are a robust model of neuro-inflammation, found that the glial derived pro-inflammatory response can be serially propagated between astrocytes and microglia following a single inflammatory insult, and that glial derived inflammatory factors are neurotoxic. Using these assays, I identified the anti-inflammatory and neuro-protective effects of flavonoid apigenin, an inducer of orphan nuclear receptor Nurr1, whose dual role as both neuro- protective and anti-inflammatory renders it an ideal target for therapeutic intervention in PD. The purpose of this project is to elucidate the role of inflammation in PD and identify key molecular events involved at early stages in PD to exploit as potential targets for therapeutic intervention. These results are important because they establish an in vitro model that enables investigation into the inflammatory contribution to the pathological development of PD, and identification of novel therapeutic compounds

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