Investigating DNA repair mechanisms in aging adult stem cells

Overview

When we age the DNA repair systems of our cells become down regulated. This results in reduced DNA repair capacity, enhanced rates of mutation load and may lead to the development of chronic aging-associated diseases including osteoporosis, Alzheimer's and cancer(1). So it is no surprise that genome instability and stem cell exhaustion, which also strongly correlates with the accumulation of DNA damage, are considered hallmarks of aging(2).

However, we still lack a clear understanding on how the decrease in DNA repair fidelity affects adult stem cells and their ability to contribute to tissue maintenance and regeneration. We also lack a comprehensive understanding of which specific pathways and proteins are involved in the DNA repair of skeletal stem cells and how the decline of repair processes with age contributes to musculoskeletal diseases such as osteoporosis and osteoarthritis.

This project is therefore aimed at characterising the DNA damage responses in young and aged skeletal progenitor cells and how the DNA repair mechanism are affected by cell cycle exit and differentiation.

Aims

• Comparison of DNA repair processes in bone marrow-derived mesenchymal stromal cells (MSC) derived from young and old donors in response to oxidative agents and irradiation.
• Characterisation of the main DNA repair processes in dividing and non-dividing (differentiating) MSC in response to DNA damage.

Approaches, skills and techniques

• Culture and transfection of human adult stem cells incl. differentiation in 3D culture models(3).
• Immunofluorescence staining and high-throughput confocal microscopy.
• Other biological and biochemical techniques such as Western blotting, life dead assays, qPCR.

Outcomes

The project will increase our understanding of how changes in DNA repair pathways affect the aging of adult stem cells. When successful, data from this project will identify potential drug targets in the treatment of aging-associated diseases such as osteoporosis and osteoarthritis. 

Required skills and experience

Skills and knowledge in cell biology and biochemistry would be beneficial.

Keywords

• Musculoskeletal Disease
• Osteoporosis
• Osteoarthritis
• DNA Repair Systems
• Mesenchymal stem/stormal cells (MSC)
• Stem Cell Differentiation
• Three-dimensional 3D cell culture systems

Contact

Contact the supervisor for more information.