As of now, there are only symptomatic treatments for patients with Parkinson's disease (PD) but no effective means by which to slow or halt the progression of PD, which occurs at a rate of 5 to 7%, resulting in significant disability from motor and non-motor symptoms. A chronic, on-going cycle of inflammation is believed to contribute to the loss of dopaminergic neurons in PD, leading to disease progression. Our research at the University of Queensland recently demonstrated that activation of the NLRP3 inflammasome is a key driver of disease progression in PD. Resolving this cycle of inflammation and neuronal damage is considered to be one of the most promising therapeutic approaches by which to slow PD progression. This project will evaluate a novel therapeutic strategy by which to activate endogenous negative regulators of the NLRP3 inflammasome in immune cells to mitigate both chronic inflammation and dopaminergic neuronal death. Our initial studies suggest that these protective pathways, which normally function to regulate and limit inflammation, are substantially reduced in people with Parkinson’s and also in animal models of the disease. Our studies will therefore evaluate if restoration or activation of these protective pathways can limit inflammation and dopaminergic neuron death. We will use experimental models of Parkinson’s disease, human patient studies and pharmacological agents to evaluate the effectiveness of our proposed therapeutic strategy. The majority of therapeutic strategies targeting inflammation in PD have aimed to directly block pro-inflammatory mediators and mechanisms that contribute to dopaminergic neuron loss in the brain. To date however, these therapeutic strategies have had limited success in clinical trials for PD. Our novel and innovative approach will instead aim to activate and restore endogenous protective signaling mechanisms that function to effectively resolve and limit inflammation. Based on our findings that these protective mechanisms are lost in PD, the results from our proposed work will provide vital proof of concept evidence for clinical translation of this therapeutic approach for disease modification in PD.