PhD Studentship: Phenotypic metabolic profiling of motor neurone disease cells models.

University of Sheffield - Neuroscience

Motor neuron disease (MND) is an adult onset disorder involving the death of motor neurons that interact with skeletal and bulbar muscles. Age is a significant risk factor, with patients surviving typically no more than 2-3 years after symptom onset. Due to the complex, multi-factorial heterogeneity of the disease there is currently no cure. Metabolic dysfunction plays a key role in MND disease progression. In healthy individuals, energy intake is in balance with expenditure, but this is not the case in MND (1). There is evidence that in many patients the normal balance between energy intake and expenditure is tipped towards expenditure. This “hypermetabolism”, coupled with defective and inefficient energy generation at a cellular level leads to weight loss, malnutrition and an energy deficit in the central nervous system. It is unclear why this is the case and there are no specific dietary recommendations for patients.

Project Aims

To understand how MND alters the ability of cells to mobilise and use nutrient sources such as carbohydrates, nucleosides or carboxylic acids to create energy in times of high demand. This will allow us to identify any disrupted pathways and use nutrient supplementation to try to restore the pathway in question or bypass the problem by finding nutrients that can directly stimulate the energy generating pathways in the cell.

Methodology

We have developed an assay that simultaneously measures how cells metabolise 92 different energy generating nutrients. Using primary cells from MND patients, we will identify nutrients that have altered metabolism compared to healthy controls with our state of the art Omnilog™ metabolic profiling system. We will then assess how supplementation of these identified nutrients affects metabolic flux and energy output in MND cell models. Furthermore, we will determine whether nutrient supplementation can reduce certain pathophysiogical mechanisms that are a hallmark of MND such as oxidative and ER stress.

Goals

In the long term, we aim to identify dysfunctional metabolic pathways for therapeutic intervention, to find disease markers to aid diagnosis and to develop rational approaches for nutritional supplementation to support healthy motor neurone metabolism. This will benefit patients by counteracting the energy deficit, stabilising body weight and improving motor neuronal health to slow the course of the disease.

Techniques

The project will involve

  1. Tissue culture of primary patient cells including induced neuronal progenitor derived stem cell neurons and astrocytes.
  2. In depth metabolic biochemical analysis using equipment such as an Omnilog metabolic profiling system (Biolog) and an XF bioanalyser (Seahorse Bioscience).
  3. General biochemical techniques such as western blotting oxidative stress assays and ATP assays.
  4. Data analysis of datasets using Qlucore and Graphpad Prism.

References

  1. Dupuis L., Pradat P.F., Ludolph A.C., Loeffler J.P. (2011). Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol. 10, 75.

The Faculty of Medicine, Dentistry & Health Doctoral Academy Scholarships cover Home/EU fee and RCUK rate stipend for three years. Overseas students may apply but will need to fund the difference between the Home and Overseas fee from another source.

Proposed start date: October 2017

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Type / Role:

PhD

Location(s):

Northern England