Mitochondrial phenotyping in patient derived models of motor neuron disease (MND) to identify novel targets for therapeutic modulation.
Dr Heather Mortiboys
Dr Scott Allen
Prof PJ Shaw
No more applications being accepted
Funded PhD Project (European/UK Students Only)
This PhD project seeks to explore the mitochondria as a therapeutic target in Motor Neuron Disease (MND). We will utilise state of the art patient derived cell models to investigate several aspects of mitochondrial function, recycling, DNA, metabolic interactions and morphology. We will then also investigate the same pathways in Drosophila models of MND developed by our collaborator, Prof Daniela Zarnescu at the University of Arizona, USA. The PhD student will spend time in the laboratory in Arizona to learn skills and make mitochondrial assessments in Drosophila models. Upon returning to Sheffield, these skills and knowledge will then be applied to the patient derived cells in order to test potential therapeutics against identified mitochondrial targets. This PhD offers a fantastic and exciting experience for the student to gain training at two excellent research centres (SITraN, at University of Sheffield and University of Arizona, USA). The training will include use of induced neuronal progenitor cells and differentiation into neurons and use of various Drosophila models. Furthermore the project is positioned to identify potential targets and molecules to progress through a translational pipeline to the clinic for MND offering a unique PhD experience.
Background: Motor Neuron Disease (MND) is an adult-onset neurodegenerative disease, with progressive failure of the neuromuscular system, typically causing death within 2–3 years of symptom onset. There is currently no cure. MND is associated with metabolic dysfunction, which may influence disease progression as the metabolic pathways are highly susceptible to the disease process. Increased reactive oxygen species production, mitochondrial uncoupling and membrane depolarization can lead to electron transport chain (ETC) dysfunction and reduced ATP generation in the central nervous system (CNS). Energetically, neurons are supported predominantly by oligodendrocytes and astrocytes. Astrocytes play an important role in MND disease progression via various mechanisms including reduced lactate release. Induced neuronal progenitor cell (iNPC) derived iAstrocytes from MND patients have been shown to cause toxicity to motor neurons in co-culture. Furthermore, the supervisory team have used this unique disease model to uncover novel targets of catabolic metabolic function in MND. Investigating in depth mitochondrial function in these heterogeneous human models using targeted screening approaches has the ability to link carbohydrate metabolism dysfunction to energy production defects in MND.
A systematic understanding of the mitochondrial abnormalities in specific cell types derived from MND patients will provide two key advances in the field; firstly an increased understanding of disease mechanisms in two relevant cell types, motor neurons and astrocytes and secondly; the identification of novel targets which can be therapeutically manipulated. Importantly this project will then be able to validate pathways and targets in in vivo models in collaboration with the US partner. This approach bridges the gap between environmental influences on the genome and the heterogenic functional outcomes which has so far reduced our translational efficacy in the disease.
Hypothesis: Mitochondrial abnormalities are drivers of disease pathology in MND; and therefore will provide viable therapeutic targets.
Aims and objectives/Scientific Approach: The supervisors have built a significant amount of expertise in modelling of human disease using patient derived cells, mitochondrial phenotyping across multiple mitochondrial functions and more broadly metabolic screening. The approach of this project will bring together patient derived and in vivo approaches in order to benefit our understanding of mechanisms driving disease pathology in MND. This will then be used in the translational pipeline to investigate novel therapeutic targets for MND.
Dr Jeff Wadsworth – Battelle PhD studentship; stipend according to RCUK rates
Candidates must have a first or upper second class honors degree or significant research experience. (Experience of cell culture is advantageous).
Proposed start date: October 2020 with potential to change depending on Covid-19 situation
When applying please clearly state the prospective main supervisor (Dr Heather Mortiboys) in the respective box and select Neuroscience as the department.