Studying the mechanisms of novel therapeutic compounds for Parkinson's Disease in complimentary in vitro and in vivo models

This project is a collaboration between two supervisors from the Neuroscience department at University of Sheffield, an industrial partner and two collaborators brining in vivo expertise from Florida and Oregon, USA. The industrial partner has already agreed to the MRC iCase studentship terms and sent a letter of collaboration to confirm. The project builds upon existing work in the laboratories of the supervisors on Parkinson's disease. We were the first group worldwide to report mitochondrial dysfunction in peripheral patient cells from patients with genetic forms of Parkinson's disease. Subsequently, we undertook the first ever drug screen using patient cells in Parkinson's disease which focused on compounds which can provide mitochondrial improvement. Subsequent to this the primary supervisor has established more advanced compound screens and complimentary patient derived neuron models for testing prospective therapeutics. In a collaboration with the industrial partner we have screened ~200 novel compounds in the patient derived fibroblasts and neurons. Based upon the data from these assays compounds have been selected for additional testing in animal models of Parkinson's disease. For this we initiated a collaboration with two leading research laboratories, one with a genetic mouse model of Parkinson's; the other with a chronic toxin induced model of Parkinson's. This PhD student project will aim to fully investigate the mechanism with which the selected compounds are producing a recovery effect in these complimentary models of Parkinson's. The project will include, not only time at the industrial partner but also at the collaborator laboratories in Florida and Oregon. This will enable the student to fully investigate the mechanistic pathways activated by these compounds in patient derived neurons in Sheffield (both genetic and sporadic forms), in a genetic mouse model and a toxin induced animal model. As well as complimentary models, complimentary methods will be used across these models to identify the signalling pathways activated by these compounds and their clinical relevance. The patient cells we have in Sheffield have the same mutation as the one introduced in the genetic mouse model; we have already established many of the same mitochondrial abnormalities are present in the patient neurons and both the genetic and toxin induced animal models. Therefore we hypothesise using these models to study the activation pathways of novel compounds will provide excellent, varied scientific training for the PhD student as well as clinically relevant data for Parkinson's Disease to translate laboratory findings to a meaningful clinical outcome.