Prof S Cragg
No more applications being accepted
Funded PhD Project (European/UK Students Only)
About the Project
Lead supervisor: Prof Stephanie Cragg, Department of Physiology, Anatomy and Genetics, Oxford (DPAG)
Commercial partner: Cerevance Ltd, Cambridge, UK
Parkinson’s disease is a progressive degenerative disorder, with debilitating movement problems that arise from the demise of nigrostriatal dopamine neurons and striatal dopamine transmission. Current strategies to restore dopamine are limited, and the mainstay of therapy, L-DOPA, has disabling side effects such as dyskinesias that prevent its long-term use. Therefore, there is a need to identify new treatments. Strategies are needed that can either slow disease progression, treat symptoms or treat side effects.
Nigrostriatal dopamine neurons have unique neurobiology. They have the most branched axonal arbours yet documented for CNS neurons. In turn, mechanisms located directly on dopamine axons powerfully regulate the striatal release of dopamine. New insights indicate that these mechanisms can critically determine dopamine release over and above activity in dopamine neuron soma. Axonal mechanisms might therefore offer novel and extensive opportunities for therapeutic benefit in Parkinson’s disease that are not currently being fully explored or exploited. This project will apply new and emerging technologies to explore dopamine axons as targets for new therapies.
In this project, we will explore and identify new strategies to govern dopamine transmission in striatum that could provide new potential targets for Parkinson’s therapy. We will use our expertise in methods to monitor dopamine transmission and neuronal activity in order to identify effects of underexplored neuromodulatory receptors that are present and also, of new and emerging candidate receptors and signalling pathways. To identify new candidate molecular mechanisms, we will exploit a powerful new technology platform at Cerevance for analysis of human dopamine neurons, alongside analysis of mouse dopamine neurons in transgenic models of Parkinson’s disease developed at the Oxford Parkinson’s Disease Centre. Targets will include those found to be enriched in human nigrostriatal neurons as well as those found to be modified in mouse dopamine neurons in PD models. We will identify the impact of these target mechanisms on dopamine synapse and neuron function in brain slices and in vivo,aided by pharmacological tools and by targeted manipulation of cell activity e.g. using optogenetics, and will have the opportunity to explore new pipeline ligands in development at Cerevance
The project capitalizes on the complementary strength and interests of Oxford and Cerevance in neurodegenerative research, and provides an opportunity to train a student in state-of-the-art skills in whole organism work and drug development.
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