Primary Supervisor: Dr Sarah Aldred, School of Sport, Exercise and Rehabilitation Sciences
Secondary supervisor: Dr Eric Hill, Aston University
PhD project title: Stem cell models to study human brain health
University of Registration: University of Birmingham
Advances in stem cell biology have enabled new methodologies with the unique ability to manipulate the human central nervous system (CNS), and have allowed the exploration of cell health and disease modelling with greater relevance to human tissue than previously possible. Amyloid precursor protein (APP) is a transmembrane protein found in many cell types around the body, most notably in brain cells such as neurons and synapses. APP processing is crucial to brain health. APP cleavage can be initiated by two different enzymes. One liberates a neuroprotective protein fragment, while the other causes protein fragments that are involved in neurodegeneration to be formed.
We have developed a model cell system using induced Pluripotent Stem Cell (iPSC) derived cortical neurons. Using these cells we have been able to establish the presence of APP, and both enzymes involved in the fate of APP (the α -secretase ADAM10 and the β-secretase BACE-1). We now need to understand much more about this processing pathway to properly understand the factors that affect brain health. We don’t yet know what factors influence which secretase is more active, for example. Studies have shown that lifestyle factors can affect the activity of secretase enzymes. For example, exercise can increase the activity of ADAM10. Diet may also affect secretase activity, as can drug use. Considering that all of these factors affect metabolism, it is highly likely that the metabolic state of the cell will affect secretase activity.
If we are able to understand more about APP processing, better characterise protein interactions within the cell and establish the effect of metabolic flux and subsequent shift in redox status in the cell, we will learn more about the factors that can drive neuroprotection and ultimately brain health.
In this project you will use human iPSC-derived neuron and astrocyte co-cultures to characterise the APP processing pathway. You will investigate potential factors that might influence activity of the different secretase enzymes. You will investigate the conditions that affect APP processing to understand how APP processing could be manipulated to benefit brain health in humans.
BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and Behaviour
Techniques that will be undertaken during the project:
- induced Pluripotent Stem Cell derivatisation and Culture
- Western Blottting and Immunoassays
- Fluorescent (Fluo4-AM) calcium imaging
Contact: Dr Sarah Aldred, University of Birmingham