Investigating age-related biochemical changes in motor neurons using an induced pluripotent stem cell in vitro model
About the Project
The studentship aims to develop an in vitro model of human motor neurons, which can be used to investigate age-related impairment of motor neuron function and identify new treatments that can be used to treat chronic diseases associated with ageing.
About this opportunity
Human sarcopenia that progresses as an age-related decline in muscle mass and function leads to frailty associated with increased incidence of falls and hospitalisation. Loss of structural muscle fibres also occurs with loss of motor units and dysregulation of the neuromuscular junction (NMJ), impairing efficient and effective transmission of action potentials from nerve to muscle.
Understanding of the molecular and biochemical changes that occur in motor neurons during ageing will enable the development of new therapeutic interventions that can delay or prevent NMJ degeneration and therefore reduce the progression of sarcopenia and its clinical impacts.
Induced pluripotent stem cells (IPSCs) are a pluripotent stem cell population generated by reprogramming somatic cells. Through their properties of self-renewal and ability to differentiate to multiple cell types, IPSCs are an important tool in developmental and disease modelling. The aim of this project is to develop and characterise an IPSC in vitro model of motor neurons that enables the investigation of molecular and biochemical changes that occur during ageing.
We hypothesise that (a) IPSC-derived neural cells can be differentiated into motor neurons that exhibit phenotypic and functional properties of human primary neruons, and (b) molecular and biochemical changes within IPSC-motor neuron model will elucidate the biological pathways that are regulated during ageing and their effect on NMJ function.
The aims of the studentship project will be:
- Aim 1 – to develop an IPSC-motor neuron in vitro model and characterise for transcriptomic phenotype and functional action potential using a combination of gene and protein expression techniques and measurement of ion channel function.
- Aim 2 – to investigating the effect of ageing on in vitro IPSC-motor neuron phenotype and function. IPSC-motor neuron function will be measured by MEA analyses in response to pro-inflammatory stimuli that are known causative agents of age-related neuropathies.
The project will include a multidisciplinary approach with training provided in the maintenance and differentiation of induced pluripotent stem cells to motor neurons, and their characterisation using molecular biology techniques to measure gene (quantitative PCR) and protein expression (ELISA), immunocytochemistry and Western blotting. Metabolic function of the cells will be measured in response to inflammatory mediators using multi-omics techniques that include transcriptomics and metabolomics (NMR and mass spectrometry) with real-time bioenergetic measurements made by Seahorse analyser. Bioinformatic strategies will be employed to identify novel pathways that are regulated by inflammatory mediators, and which are indicative of being causative in inflammatory disease.
Email CV and cover letter to Dr Rachel Oldershaw, Rachel.oldershaw@liverpool.ac.uk
Funding Notes
The research cost associated with the project is £15000 per annum for the purchase of laboratory reagents, including molecular biology and biochemical reagents, the use of shared research facilities for multi-omics analyses and licences for software used in bioinformatics.
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