- Vacancy Reference Number
- Astrocytes & metabolism MIBTP 2024
- Closing Date
- 16 Jan 2025
- Salary
- Studentships cover fees (the cost of the UK fee rate), a tax-free annual stipend, a travel & conference budget, a generous consumables budget, and the use MacBook Pro for the duration of the programme
- Address
- University of Birmingham, Department of Inflammation and Ageing.
- Duration
- 4 years
About the Project
The human brain is always active. The brain consumes 20% of total body energy available, but makes up just 2% of total body weight. A large portion of this energy demand is dedicated to neural signalling processes and the maintainance of ionic gradients which are essential for cell to cell communication. The supply of energy is crucial for brain activity. The high energy demands of the brain makes it particularly susceptible to the dysregulation of bioenergetic processes, redox imbalance, and reduced blood flow or nutrient supply. Astrocytes are the most common cell type in the human brain, and are thought to be capable of supporting and regulating neuronal functions. Astrocytes can take up neurotransmitters, supply neurons with metabolites and respond to inflammatory processes. Astrocytes are also unique in that, they favour aerobic glycolysis and can store glycogen. This is important to enable neuronal function to be sustained under conditions of stress. Dysfunction of astrocytes and alteration in astrocyte metabolism has been implicated in cognitive decline and in neurodegenerative diseases, yet we still do not fully understand their role in supporting neuronal function in the healthy brain. To fully understand how the human brain develops and subsequently functions, it has been critical to create model systems that enable reliable, functionally relevant, and controllable experimentation. Induced pluripotent stem cell (iPSC)-derived models of the brain allow us to achieve this. In previous research, we have created neuron-astrocyte mixed culture models from patient iPSC to investigate how astrocyte metabolism supports neuronal functions. Therefore, these iPSC-derived CNS models offer a tractable system in which to investigate the involvement of neuronal-glial interactions in human brain functions.
Objectives: To use iPSC-derived CNS models to investigate the metabolic interaction between Astrocytes and Neurons to sustain synaptic activity.
1. Characterise substrate utilisation capacity in astrocytes for energy production.
2. Investigate whether neuronal activity can stimulate alterations in astrocyte substrate utilisation and metabolic function.
3. Interrogate signalling cascades that regulate the link between synaptic activity and alterations in astrocyte-neuron metabolic coupling.
Methods:
Through the use of iPSC reprogramming, neuronal and astrocytic cells will be created. Cell lineage will be confirmed by qPCR and immunocytochemical staining for typical markers at neural stem cells, neurons and astrocytes. For objective 1, astrocytes will be examined under modified culture conditions (hypoxia, hypoglycaemia, lipid stress) for metabolic flexibility using extracellular flux (seahorse XF) and metabolite analysis. This will provide a deep understanding of how human astrocytes function and respond to ‘environmental’ stimulus. Objective 2 will use microelectrode array (MEA) electrophysiology to understand how electrical activity is impacted by neuronal-astrocyte interactions.
To achieve this, we will compare levels of neuronal activity between co-cultures of neurons and astrocytes with neuronal monocultures. To understand the signalling pathways governing astrocyte-neuronal metabolic coupling in objective 3, specific signalling pathways will be stimulated or blocked that link cellular energy sensing to the uptake of metabolites used to generate ATP, for example AMPK, PI3K, insulin receptors and glucose uptake transporters.
Further Information
This project is funded by the BBSRC Doctoral Training Programme as part of the Midlands Integrated Biosciences Training Partnership. International students may apply and overseas fees will be waived. However, you will still be expected to pay for your visa and health insurance surcharge. There is also a maximum of 30% of overseas students into the programme as stipulated by the funder.
For more information: https://warwick.ac.uk/fac/cross_fac/mibtp/
Contact Details
Project supervisors:
Prof Sarah Aldred - s.aldred.1@bham.ac.uk
Dr Richard Elsworthy - r.j.elsworthy@bham.ac.uk
Dr Daniel Fulton - d.fulton@bham.ac.uk
Informal enquiries, please contact the project supervisors using the emails above
