Principal Supervisor: Prof. Sarah AldredLink opens in a new window

Co-supervisor: Dr Martin Whitham

Other supervisors: Dr Richard Elsworthy, Dr Eric Hill (Aston University)

PhD project title: Ageing, extracellular vesicles, and brain health

University of Registration: University of Birmingham

Project outline:
General Background:

Exercise is beneficial for health! Indeed exercise promotes healthy ageing. Regular exercise can increase the number of years we live in good health, reduce the risk of disease onset, and promote a better quality of life. Yet, we still do not fully understand the mechanisms by which exercise conveys these benefits, especially in the context of brain health. One potential mechanism is via the release of small extracellular vesicles from exercising muscle tissue. These vesicles may deliver cargo proteins to the brain that function as antioxidant enzymes or inhibitors of cell ageing. During a bout of exercise, the contents of small vesicles change compared to the resting state. In our previous research, we have demonstrated vesicles released during exercise contain greater levels of neuroprotective signalling molecules and an altered composition of proteins. However, the role of extracellular vesicles and the effect of their contents on brain health is not known. Thus, research into the role of small extracellular vesicles in healthy ageing is needed.

To investigate this in the brain is incredibly difficult, do to the lack of accessibility of the brain. This project will use the latest advances in stem cell biology and new methodologies that have the unique capacity to manipulate the human central nervous system (CNS). Through a process of reprogramming induced pluripotent stem cells, we can generate neurons and glial cells of the brain. These reprogrammed cells recapture the donors genetic background and develop into functional, and physiologically relevant models of the human brain. The research team working on this project has expertise in generating these cellular models in both healthy and disease states. For this project, we will study the effects extracellular vesicles on healthy brain function and gain insight into how exercise may signal to improve brain health. These methods of cell culture allow the exploration of the brain with greater relevance to human tissue than animal models or post-mortem tissue. In particular we will focus on generating functioning neurons and glial cells in isolation and in mixed co-culture models.

Objectives:

The overall aim of this project is to develop a better understanding of how ageing effects Extracellular Vesicle cargo in response to exercise and how this may impact on brain health. More specifically this aims of this project are:

• To investigate differences in EV proteome across the (healthy ageing) lifespan.

• To compare the effects of exercise on EV cargo and whether ageing impacts the exercise response.

• To observe the treatment effect of peripherally isolated EVs on neuronal function, by utilising induced pluripotent stem cell models of the brain.

Methods:

In this project you will begin by isolating and characterising small extracellular vesicles from individuals across the life span and following acute exercise bouts to understand how small vesicle contents are altered. You will also learn how to culture induced pluripotent stem cells and differentiate them into distinct brain cell types. From here, you will develop a novel treatment plan to investigate the effects of small extracellular vesicles on neuronal and astrocyte function, with a goal to generate data on how this may improve overall brain health. During this time you will gain a wide range of experimental skills, from flow cytometry through to cellular metabolic functional analysis.

 

References:

McIlvenna, L.C. and Whitham, M., 2022. Exercise, healthy ageing, and the potential role of small extracellular vesicles. The Journal of Physiology.

Elsworthy, R.J., King, M.C., Grainger, A., Fisher, E., Crowe, J.A., Alqattan, S., Ludlam, A., Hill, E.J. and Aldred, S., 2021. Amyloid-β precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation. Molecular and Cellular Neuroscience, 114, p.103631.

Elsworthy, R.J., Crowe, J.A., King, M.C., Dunleavy, C., Fisher, E., Ludlam, A., Parri, H.R., Hill, E.J. and Aldred, S., 2022. The effect of citalopram treatment on amyloid-β precursor protein processing and oxidative stress in human hNSC-derived neurons. Translational psychiatry, 12(1), pp.1-7.

BBSRC Strategic Research Priority: Integrated Understanding of Health - Ageing

Techniques that will be undertaken during the project:

Blood fraction preparation and EV isolation (optional Phlebotomy training)

Proteomics

induced Pluripotent Stem Cell derivatisation and Culture

Directed differentiation of stem cells into cortical cell types

Immunoassays and microplate-based experiments (flow cytometry, Western blotting, ELISA)

Microscopy (Confocal, phase-contrast, fluorescence with Immunocytochemistry)

Seahorse XF analysis

 

Contact: Prof. Sarah AldredLink opens in a new window