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Stem cell models to study human neurodevelopment and brain health

Primary Supervisor: Professor Sarah Aldred, School of Sport, Exercise and Rehabilitation Sciences

Secondary supervisor: Dr Eric Hill, Aston University

Tertiary Supervisor: Dr Richard Elsworthy, UoB, ECR

PhD project title: Stem cell models to study human neurodevelopment and brain health

University of Registration: University of Birmingham

Project outline:

The brain is so difficult to get at! It is incredibly challenging to study neurodevelopment and the factors that affect cell function in the brain. This project will use the latest advances in stem cell biology and new methodologies that have the unique ability to manipulate the human central nervous system (CNS). These methods allow the exploration of neurodevelopmental modelling with greater relevance to human tissue than previously possible.

‘a disintegrin and metalloproteinase’ (ADAM10) is an enzyme involved in many cell regulatory processes, but its primary function is thought to be in neurodevelopment. Cell to cell adhesion and synaptic pruning are critical for the establishment of early cortical development and are key roles associated with ADAM10 function. However, ADAM10 relies on being in close proximity to its targets and so, proper localisation, activity and maturation of the enzyme are fundamental to its action.

We have developed a model brain cell system using induced Pluripotent Stem Cell (iPSC) derived cortical neurons, astrocytes and microglia. We have established the presence and function of ADAM10 in our model system. We now need to understand much more about ADAM10 and the role it plays in normal neurodevelopment and the development of a healthy brain. For example, we don’t yet know how ADAM10 colocalises with its target proteins in order to cleave them. Nor do we understand how ADAM10 might enable neural circuitry, to for example, facilitate the development of mature synapses.

If we are able to understand more about ADAM10 protein processing to better characterise protein interactions within the cell, we will learn more about the factors that can drive neurodevelopment and ultimately brain health.

In this project you will use human iPSC-derived neuron and astrocyte mono and co-culture systems to characterise the ADAM10 processing pathways. You will investigate potential factors that might influence activity of the enzyme as well as investigate the effect of gene knockout/ knockdown. You will investigate the conditions that affect ADAM10 associated pathways to understand how neurodevelopment and ultimately brain health is affected in humans.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour & Stem Cells  

    Techniques that will be undertaken during the project:

    • Induced Pluripotent Stem Cell derivatisation and Culture
    • Directed differentiation of stem cells into cortical cell types
    • Flow cytometric analysis
    • Western Blotting and Immunoassays
    • Fluorescent (Fluo4-AM) calcium and Immunocytochemistry imaging

    Contact: Professor Sarah Aldred, University of Birmingham